Pub Date : 2025-12-01DOI: 10.1016/s2352-3026(25)00288-1
Arnon P Kater,Sabina Kersting,Julie M Dubois,Bronno van der Holt,Caspar da Cunha-Bang,Doreen Te Raa,Cecile Idink,Fransien de Boer,Jolanda Droogendijk,Koen de Heer,Leonie van der Burg,Marten R Nijziel,Lidwien Tick,Henriette Levenga,Matthijs Silbermann,Inge Ludwig,Aart Beeker,Mar Bellido,Johan A Dobber,Ludo M Evers,Anne-Marie van der Kevie-Kersemaekers,Clemens Mellink,Ine Meulendijks,Sonia Cunha,Martine Abrahamse-Testroote,Gerben Zwezerijnen,Josée Zijlstra,Carsten U Niemann,Mark-David Levin
BACKGROUNDTriplet regimens combining a Bruton's tyrosine kinase inhibitor, B-cell lymphoma 2 inhibitor, and anti-CD20 antibody are among the most effective first-line treatments for chronic lymphocytic leukaemia, but come with substantial toxicity. We investigated whether fixed-duration ibrutinib plus venetoclax, followed by ibrutinib plus obinutuzumab intensification for individuals with residual disease only, could offer a more tailored and less toxic alternative.METHODSHOVON158/NEXT STEP was an open-label, phase 2 study at 17 hospitals in the Netherlands and Denmark. Eligible participants were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, requiring treatment according to the International Workshop on Chronic Lymphocytic Leukemia, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Participants with complete remission or complete remission with incomplete count recovery and undetectable measurable residual disease (<10-4 uMRD4) in bone marrow after 15 28-day cycles of oral ibrutinib (420 mg once daily) plus oral venetoclax (5-weekly ramp-up from cycle 4 up to 400 mg once daily) discontinued treatment; all other participants received an additional six cycles of ibrutinib plus obinutuzumab intravenously (1000 mg on days 1, 2, 8, and 15 of cycle 1 and day 1 of cycles 2-6). The primary endpoint was bone marrow uMRD4 complete remission or complete remission with incomplete count recovery 3 months after the end of intensification with ibrutinib plus obinutuzumab in participants who were not in complete remission or who had detectable measurable residual disease (MRD) on ibrutinib plus venetoclax, and analysed according to the modified intention-to-treat principle excluding participants retrospectively deemed ineligible. All participants who received at least one dose of the study drug were included in the safety assessment. This report is the primary endpoint analysis of this trial, which is registered at ClinicalTrials.gov, NCT04639362, and is ongoing.FINDINGSBetween Dec 29, 2020, and Aug 20, 2021, 85 participants were enrolled, 84 of whom were eligible (56 male and 28 female). The intensification group consisted of 55 participants (37 male and 18 female) and the observation group consisted of 17 participants (11 male and six female). 3 months after the end of ibrutinib plus obinutuzumab treatment, 33 (60%; 90% CI 48-71) of 55 participants had bone marrow uMRD4 complete remission or complete remission with incomplete count recovery. The most common grade 3-4 adverse events during ibrutinib plus venetoclax treatment were neutropenia (36 [43%] of 84 participants) and infections (19 [23%] participants), and the most common during ibrutinib plus obinutuzumab treatment were neutropenia and thrombocytopenia (five [10%] of 52 participants) and nervous system disorders (4 [8%] participants). Serious adverse events occurred in 28 (33%) participants receiving ibrutinib plus venetoclax and seven (13%)
{"title":"Fixed-duration ibrutinib-venetoclax with MRD-guided ibrutinib-obinutuzumab intensification in first-line chronic lymphocytic leukaemia (HOVON 158/NEXT STEP): primary analysis of a multicentre, open-label, phase 2 trial.","authors":"Arnon P Kater,Sabina Kersting,Julie M Dubois,Bronno van der Holt,Caspar da Cunha-Bang,Doreen Te Raa,Cecile Idink,Fransien de Boer,Jolanda Droogendijk,Koen de Heer,Leonie van der Burg,Marten R Nijziel,Lidwien Tick,Henriette Levenga,Matthijs Silbermann,Inge Ludwig,Aart Beeker,Mar Bellido,Johan A Dobber,Ludo M Evers,Anne-Marie van der Kevie-Kersemaekers,Clemens Mellink,Ine Meulendijks,Sonia Cunha,Martine Abrahamse-Testroote,Gerben Zwezerijnen,Josée Zijlstra,Carsten U Niemann,Mark-David Levin","doi":"10.1016/s2352-3026(25)00288-1","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00288-1","url":null,"abstract":"BACKGROUNDTriplet regimens combining a Bruton's tyrosine kinase inhibitor, B-cell lymphoma 2 inhibitor, and anti-CD20 antibody are among the most effective first-line treatments for chronic lymphocytic leukaemia, but come with substantial toxicity. We investigated whether fixed-duration ibrutinib plus venetoclax, followed by ibrutinib plus obinutuzumab intensification for individuals with residual disease only, could offer a more tailored and less toxic alternative.METHODSHOVON158/NEXT STEP was an open-label, phase 2 study at 17 hospitals in the Netherlands and Denmark. Eligible participants were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, requiring treatment according to the International Workshop on Chronic Lymphocytic Leukemia, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Participants with complete remission or complete remission with incomplete count recovery and undetectable measurable residual disease (<10-4 uMRD4) in bone marrow after 15 28-day cycles of oral ibrutinib (420 mg once daily) plus oral venetoclax (5-weekly ramp-up from cycle 4 up to 400 mg once daily) discontinued treatment; all other participants received an additional six cycles of ibrutinib plus obinutuzumab intravenously (1000 mg on days 1, 2, 8, and 15 of cycle 1 and day 1 of cycles 2-6). The primary endpoint was bone marrow uMRD4 complete remission or complete remission with incomplete count recovery 3 months after the end of intensification with ibrutinib plus obinutuzumab in participants who were not in complete remission or who had detectable measurable residual disease (MRD) on ibrutinib plus venetoclax, and analysed according to the modified intention-to-treat principle excluding participants retrospectively deemed ineligible. All participants who received at least one dose of the study drug were included in the safety assessment. This report is the primary endpoint analysis of this trial, which is registered at ClinicalTrials.gov, NCT04639362, and is ongoing.FINDINGSBetween Dec 29, 2020, and Aug 20, 2021, 85 participants were enrolled, 84 of whom were eligible (56 male and 28 female). The intensification group consisted of 55 participants (37 male and 18 female) and the observation group consisted of 17 participants (11 male and six female). 3 months after the end of ibrutinib plus obinutuzumab treatment, 33 (60%; 90% CI 48-71) of 55 participants had bone marrow uMRD4 complete remission or complete remission with incomplete count recovery. The most common grade 3-4 adverse events during ibrutinib plus venetoclax treatment were neutropenia (36 [43%] of 84 participants) and infections (19 [23%] participants), and the most common during ibrutinib plus obinutuzumab treatment were neutropenia and thrombocytopenia (five [10%] of 52 participants) and nervous system disorders (4 [8%] participants). Serious adverse events occurred in 28 (33%) participants receiving ibrutinib plus venetoclax and seven (13%) ","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"127 1","pages":"e935-e945"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/s2352-3026(25)00282-0
Erica Koranteng,Gregory A Abel,Anoa Aidoo,Amar H Kelkar
{"title":"A communitarian approach to cell therapy and gene therapy access in low-income and middle-income countries.","authors":"Erica Koranteng,Gregory A Abel,Anoa Aidoo,Amar H Kelkar","doi":"10.1016/s2352-3026(25)00282-0","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00282-0","url":null,"abstract":"","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"28 1","pages":"e931-e932"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/s2352-3026(25)00294-7
Chan H L Esther,Eugene Bingwen Fan,Yu Yue Hew,L M Poon
Medical tourism in the field of cellular therapy has been increasing exponentially, especially in the past decade, due to multiple advances in the field. Our Viewpoint explores this growing field, with a specific focus on haematopoietic stem-cell transplantation (HSCT) and chimeric antigen receptor (CAR) T-cell therapy. We discuss the global status, regulatory challenges, and ethical considerations associated with medical tourism. We highlight benefits and drawbacks of medical tourism with regard to patient care and the impact on local health-care systems. We also address the crucial distinction between regulated, evidence-based cellular therapies and risky, unproven stem-cell tourism, which preys on vulnerable patients. We offer practical insights from our experience practicing in a regional cellular therapy hub and emphasise the importance of comprehensive patient support through a multidisciplinary team, telemedicine integration, and international collaboration to improve patient outcomes. Last, we provide perspective and suggestions on how medical tourism can be a catalyst for change within patients' countries of origin in order to improve global health-care equity.
{"title":"Medical tourism for cellular therapy: a clinical perspective.","authors":"Chan H L Esther,Eugene Bingwen Fan,Yu Yue Hew,L M Poon","doi":"10.1016/s2352-3026(25)00294-7","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00294-7","url":null,"abstract":"Medical tourism in the field of cellular therapy has been increasing exponentially, especially in the past decade, due to multiple advances in the field. Our Viewpoint explores this growing field, with a specific focus on haematopoietic stem-cell transplantation (HSCT) and chimeric antigen receptor (CAR) T-cell therapy. We discuss the global status, regulatory challenges, and ethical considerations associated with medical tourism. We highlight benefits and drawbacks of medical tourism with regard to patient care and the impact on local health-care systems. We also address the crucial distinction between regulated, evidence-based cellular therapies and risky, unproven stem-cell tourism, which preys on vulnerable patients. We offer practical insights from our experience practicing in a regional cellular therapy hub and emphasise the importance of comprehensive patient support through a multidisciplinary team, telemedicine integration, and international collaboration to improve patient outcomes. Last, we provide perspective and suggestions on how medical tourism can be a catalyst for change within patients' countries of origin in order to improve global health-care equity.","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"21 1","pages":"e978-e985"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/s2352-3026(25)00317-5
Kesso Gabrielle van Zutphen,Sufia Askari,Hans Verhoef
{"title":"Menstrual blood loss reduction to control anaemia (and more).","authors":"Kesso Gabrielle van Zutphen,Sufia Askari,Hans Verhoef","doi":"10.1016/s2352-3026(25)00317-5","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00317-5","url":null,"abstract":"","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"365 1","pages":"e929-e930"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145663962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/s2352-3026(25)00293-5
Michael Scordo,Miguel-Angel Perales,Audrey Mauguen,Andrew Lin,Binni Kunvarjee,Maria Paes Pena,Devin Mcavoy,Linh Khanh Nguyen,Molly Hogan,Nancy Chapman,Jennifer Bieler,Christina Cho,Boglarka Gyurkocza,Andrew C Harris,Barbara Spitzer,Richard J O'Reilly,Ann A Jakubowski,Richard J Lin,Esperanza B Papadopoulos,Ioannis Politikos,Doris M Ponce,Brian C Shaffer,Gunjan L Shah,Roni Tamari,Sergio A Giralt,Jaap-Jan Boelens,Kevin J Curran
BACKGROUNDEx-vivo CD34+ selected allogeneic haematopoietic cell transplantation (HCT) provides favourable chronic graft-versus-host disease (GVHD)-free relapse-free survival but is limited by delayed immune reconstitution and early non-relapse mortality. High anti-thymocyte globulin (ATG) exposure after HCT has been associated with delayed CD4+ T-cell immune reconstitution, increased non-relapse mortality, and poor overall survival.METHODSWe report the final analysis of a single-centre, phase 2 trial investigating pharmacokinetic model-based ATG (targeting <20 AU × d/mL post-HCT exposure) in participants of any age undergoing ex vivo CD34+ selected allogeneic HCT after myeloablative conditioning for haematological malignancies. Two myeloablative conditioning regimens were used at the discretion of the treating physician: the chemotherapy-based regimen (target cumulative exposure of 65 mg × h/L busulfan, 140 mg/m2 melphalan, and 150 mg/m2 fludarabine) and a high-dose total-body irradiation-based regimen (included total-body irradiation [1375 cGy], thiotepa [10 mg/kg], and cyclophosphamide [100 mg/kg]). The primary objective was an improvement in CD4+ immune reconstitution (>50 cells per μL at two consecutive timepoints by day +100) in at least 32% of the per protocol population. This study was registered with ClinicalTrials.gov (NCT04872595) and is completed.FINDINGSBetween June 14, 2021, and Nov 28, 2023, we enrolled 59 participants with haematological malignancies. Among evaluable participants (n=56), the median age was 55 years (IQR 30-63), 34 (61%) were male, 22 (39%) were female, 44 (79%) had myeloid malignancies, and 44 (79%) had received chemotherapy-only myeloablative conditioning. The median estimated ATG exposure after HCT was 10 AU × d/mL (IQR 9-11). CD4+ immune reconstitution was reached in 39 (70%) of 56 participants, meeting the study's primary endpoint. The most common grade 3 or worse adverse events were infections (103 [40%] of 259 events) and oral or gastrointestinal events (44 [17%] of 259 events). Grade 5 adverse events occurred in three participants including secondary graft failure (n=1) and multi-organ failure (n=2), with a total of four treatment-related deaths among participants.INTERPRETATIONThese results demonstrate that model-based ATG dosing promotes robust CD4+ immune reconstitution after ex vivo CD34+ selected allogeneic HCT, underscoring the potential of pharmacokinetically guided ATG as a strategy to optimise immune recovery in myeloablative, calcineurin inhibitor-free transplantation for haematological malignancies.FUNDINGUS National Cancer Institute, Memorial Sloan Kettering Cancer Center.
体内CD34+选择的同种异体造血细胞移植（HCT）提供了有利的慢性移植物抗宿主病（GVHD）无复发生存，但受到延迟免疫重建和早期非复发死亡率的限制。HCT后高抗胸腺细胞球蛋白（ATG）暴露与CD4+ t细胞免疫重建延迟、非复发死亡率增加和总生存率低相关。方法：我们报告了一项单中心2期试验的最终分析结果，该试验研究了基于ATG的药代动力学模型（在每天+100的两个连续时间点靶向50个细胞/ μL），在每个方案人群中至少占32%。该研究已在ClinicalTrials.gov注册（NCT04872595）并已完成。研究结果：在2021年6月14日至2023年11月28日期间，我们招募了59名血液恶性肿瘤患者。在可评估的参与者（n=56）中，中位年龄为55岁（IQR 30-63），男性34人（61%），女性22人（39%），44人（79%）患有髓系恶性肿瘤，44人（79%）接受过化疗-仅清除骨髓调节。HCT后ATG暴露的中位数估计为10 AU × d/mL （IQR 9-11）。56名参与者中有39人（70%）达到了CD4+免疫重建，达到了研究的主要终点。最常见的3级或更严重不良事件是感染（259例事件中103例[40%]）和口服或胃肠道事件（259例事件中44例[17%]）。3名参与者发生了5级不良事件，包括继发性移植物衰竭（n=1）和多器官衰竭（n=2），参与者中总共有4例与治疗相关的死亡。这些结果表明，基于模型的ATG剂量促进体外CD34+选择异体HCT后稳健的CD4+免疫重建，强调了药代动力学指导的ATG作为优化血液系统恶性肿瘤的清髓、无钙调磷酸酶抑制剂移植的免疫恢复策略的潜力。美国国家癌症研究所，纪念斯隆凯特琳癌症中心。
{"title":"Model-based antithymocyte globulin dosing in ex vivo CD34+ selected allogeneic haematopoietic cell transplantation: a single-centre, single-arm, phase 2 study.","authors":"Michael Scordo,Miguel-Angel Perales,Audrey Mauguen,Andrew Lin,Binni Kunvarjee,Maria Paes Pena,Devin Mcavoy,Linh Khanh Nguyen,Molly Hogan,Nancy Chapman,Jennifer Bieler,Christina Cho,Boglarka Gyurkocza,Andrew C Harris,Barbara Spitzer,Richard J O'Reilly,Ann A Jakubowski,Richard J Lin,Esperanza B Papadopoulos,Ioannis Politikos,Doris M Ponce,Brian C Shaffer,Gunjan L Shah,Roni Tamari,Sergio A Giralt,Jaap-Jan Boelens,Kevin J Curran","doi":"10.1016/s2352-3026(25)00293-5","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00293-5","url":null,"abstract":"BACKGROUNDEx-vivo CD34+ selected allogeneic haematopoietic cell transplantation (HCT) provides favourable chronic graft-versus-host disease (GVHD)-free relapse-free survival but is limited by delayed immune reconstitution and early non-relapse mortality. High anti-thymocyte globulin (ATG) exposure after HCT has been associated with delayed CD4+ T-cell immune reconstitution, increased non-relapse mortality, and poor overall survival.METHODSWe report the final analysis of a single-centre, phase 2 trial investigating pharmacokinetic model-based ATG (targeting <20 AU × d/mL post-HCT exposure) in participants of any age undergoing ex vivo CD34+ selected allogeneic HCT after myeloablative conditioning for haematological malignancies. Two myeloablative conditioning regimens were used at the discretion of the treating physician: the chemotherapy-based regimen (target cumulative exposure of 65 mg × h/L busulfan, 140 mg/m2 melphalan, and 150 mg/m2 fludarabine) and a high-dose total-body irradiation-based regimen (included total-body irradiation [1375 cGy], thiotepa [10 mg/kg], and cyclophosphamide [100 mg/kg]). The primary objective was an improvement in CD4+ immune reconstitution (>50 cells per μL at two consecutive timepoints by day +100) in at least 32% of the per protocol population. This study was registered with ClinicalTrials.gov (NCT04872595) and is completed.FINDINGSBetween June 14, 2021, and Nov 28, 2023, we enrolled 59 participants with haematological malignancies. Among evaluable participants (n=56), the median age was 55 years (IQR 30-63), 34 (61%) were male, 22 (39%) were female, 44 (79%) had myeloid malignancies, and 44 (79%) had received chemotherapy-only myeloablative conditioning. The median estimated ATG exposure after HCT was 10 AU × d/mL (IQR 9-11). CD4+ immune reconstitution was reached in 39 (70%) of 56 participants, meeting the study's primary endpoint. The most common grade 3 or worse adverse events were infections (103 [40%] of 259 events) and oral or gastrointestinal events (44 [17%] of 259 events). Grade 5 adverse events occurred in three participants including secondary graft failure (n=1) and multi-organ failure (n=2), with a total of four treatment-related deaths among participants.INTERPRETATIONThese results demonstrate that model-based ATG dosing promotes robust CD4+ immune reconstitution after ex vivo CD34+ selected allogeneic HCT, underscoring the potential of pharmacokinetically guided ATG as a strategy to optimise immune recovery in myeloablative, calcineurin inhibitor-free transplantation for haematological malignancies.FUNDINGUS National Cancer Institute, Memorial Sloan Kettering Cancer Center.","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"28 1","pages":"e956-e965"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/s2352-3026(25)00326-6
The Lancet Haematology
{"title":"Acute myeloid leukaemia at the extremes.","authors":" The Lancet Haematology","doi":"10.1016/s2352-3026(25)00326-6","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00326-6","url":null,"abstract":"","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"4 1","pages":"e927"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDPatients with relapsed or refractory T-cell acute lymphoblastic leukaemia have limited responses to conventional chemotherapy and poor prognoses. T-cell precursors exhibit high expression of BCL-2 and are sensitive to BCL-2 inhibitors. Retrospective case series have reported the successful use of venetoclax combined with chemotherapy or hypomethylating agents when treating relapsed or refractory T-cell acute lymphoblastic leukaemia. The study aimed to evaluate the activity and safety of the venetoclax plus azacitidine regimen in patients with relapsed or refractory T-cell acute lymphoblastic leukaemia.METHODSIn this single-arm, phase 2, multicentre trial, patients aged 15-70 years with relapsed or refractory T-cell acute lymphoblastic leukaemia and an Eastern Cooperative Oncology Group performance status of 0-3 were eligible. The venetoclax plus azacitidine regimen consisted of venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-21, orally) and azacitidine (75 mg/m2 per day on days 1-7, subcutaneously). The primary endpoint was overall response rate. Activity analyses were performed in the full analysis set that included all enrolled patients. This trial is registered with ClinicalTrials.gov (NCT05149378) and is complete.FINDINGSBetween Nov 28, 2021, and Dec 31, 2024, 25 patients were enrolled. The median age at enrolment was 39·0 years (IQR 27·5-56·5); 18 patients (72%) were male and seven (28%) were female; and all patients were Asian. The overall response rate was 76% (19 of 25; 36% [nine of 25] for complete remission, 16% [four of 25] for complete remission with partial haematological recovery, 16% [four of 25] for complete remission with incomplete haematological recovery, and 8% [two of 25] for morphological leukaemia-free state). As of the data cutoff (April 7, 2025), median follow-up was 31·8 months (IQR 16·2-39·3). The most common grade 3 or worse haematological adverse events were neutropenia (21 [84%] of 25), anaemia (11 [44%] of 25), febrile neutropenia (ten [40%] of 25), and thrombocytopenia (five [20%] of 25), followed by infections (three [12%] of 25). No treatment-related serious adverse events were observed and no treatment-related deaths occurred.INTERPRETATIONThe venetoclax plus azacitidine regimen showed a manageable safety profile and promising activity as salvage therapy for relapsed or refractory T-cell acute lymphoblastic leukaemia. Given the limited sample size and single-arm design nature, further confirmatory trials are warranted to validate its efficacy as a potential salvage therapy for relapsed or refractory T-cell acute lymphoblastic leukaemia.FUNDINGNational Natural Science Foundation of China.TRANSLATIONFor the Chinese translation of the abstract see Supplementary Materials section.
{"title":"Venetoclax plus azacitidine in relapsed or refractory T-cell acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 trial.","authors":"Han-Yu Cao,Hao Zhang,Yang Zhang,Xiao-Hui Hu,Li Yang,Yan-Li Yang,Yan-Ming Zhang,Bing Wu,Zhen-Qi Huang,Rui Huang,Rui-Juan Wang,Chao-Ling Wan,De-Pei Wu,Hai-Ping Dai,Sheng-Li Xue","doi":"10.1016/s2352-3026(25)00284-4","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00284-4","url":null,"abstract":"BACKGROUNDPatients with relapsed or refractory T-cell acute lymphoblastic leukaemia have limited responses to conventional chemotherapy and poor prognoses. T-cell precursors exhibit high expression of BCL-2 and are sensitive to BCL-2 inhibitors. Retrospective case series have reported the successful use of venetoclax combined with chemotherapy or hypomethylating agents when treating relapsed or refractory T-cell acute lymphoblastic leukaemia. The study aimed to evaluate the activity and safety of the venetoclax plus azacitidine regimen in patients with relapsed or refractory T-cell acute lymphoblastic leukaemia.METHODSIn this single-arm, phase 2, multicentre trial, patients aged 15-70 years with relapsed or refractory T-cell acute lymphoblastic leukaemia and an Eastern Cooperative Oncology Group performance status of 0-3 were eligible. The venetoclax plus azacitidine regimen consisted of venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-21, orally) and azacitidine (75 mg/m2 per day on days 1-7, subcutaneously). The primary endpoint was overall response rate. Activity analyses were performed in the full analysis set that included all enrolled patients. This trial is registered with ClinicalTrials.gov (NCT05149378) and is complete.FINDINGSBetween Nov 28, 2021, and Dec 31, 2024, 25 patients were enrolled. The median age at enrolment was 39·0 years (IQR 27·5-56·5); 18 patients (72%) were male and seven (28%) were female; and all patients were Asian. The overall response rate was 76% (19 of 25; 36% [nine of 25] for complete remission, 16% [four of 25] for complete remission with partial haematological recovery, 16% [four of 25] for complete remission with incomplete haematological recovery, and 8% [two of 25] for morphological leukaemia-free state). As of the data cutoff (April 7, 2025), median follow-up was 31·8 months (IQR 16·2-39·3). The most common grade 3 or worse haematological adverse events were neutropenia (21 [84%] of 25), anaemia (11 [44%] of 25), febrile neutropenia (ten [40%] of 25), and thrombocytopenia (five [20%] of 25), followed by infections (three [12%] of 25). No treatment-related serious adverse events were observed and no treatment-related deaths occurred.INTERPRETATIONThe venetoclax plus azacitidine regimen showed a manageable safety profile and promising activity as salvage therapy for relapsed or refractory T-cell acute lymphoblastic leukaemia. Given the limited sample size and single-arm design nature, further confirmatory trials are warranted to validate its efficacy as a potential salvage therapy for relapsed or refractory T-cell acute lymphoblastic leukaemia.FUNDINGNational Natural Science Foundation of China.TRANSLATIONFor the Chinese translation of the abstract see Supplementary Materials section.","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"142 1","pages":"e946-e955"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDAlthough chimeric antigen receptor (CAR) T-cell therapy has improved clinical outcomes for patients with relapsed or refractory B-cell acute lymphoblastic leukaemia, treatment resistance and relapse after remission driven by CAR T-cell dysfunction remain significant clinical challenges. To mitigate this limitation, we developed anti-CD19 CAR T cells expressing IL-10 (META 10-19) and aimed to assess their safety and activity in this patient group.METHODSWe conducted an open-label, single-arm, phase 1 study at the First Affiliated Hospital of University of Science and Technology of China, Hefei, China. Patients aged 3-70 years with relapsed or refractory B-cell acute lymphoblastic leukaemia diagnosed according to the 5th edition of WHO's Classification of Haematolymphoid Tumours and an Eastern Cooperative Oncology Group performance status score of 0-1 were eligible for inclusion. Lymphodepletion was achieved by use of intravenous fludarabine (25-30 mg/m2 per day) and intravenous cyclophosphamide (250-300 mg/m2 per day) from day -5 to -3. META 10-19 was administered intravenously in a single infusion of 0·1 × 106 or 0·2 × 106 CAR T cells per kg. The primary endpoints were safety, assessed by dose-limiting toxicity, immune effector cell-associated toxicity, and other treatment-related adverse events; and activity, assessed by clinical response rate and survival. Safety and activity were analysed in all eligible patients who received META 10-19 infusion. This study is registered with ClinicalTrials.gov, NCT05747157, and has been completed.FINDINGSBetween May 16, 2023, and July 29, 2024, 15 patients were enrolled and underwent whole-blood collection. 12 patients (median age 48 years [IQR 33-53]) received META 10-19 infusion and were included in the analyses, of whom all patients were Chinese, seven (58%) were men, and five (42%) were women. Median follow-up was 12·5 months (IQR 7·4-15·6). The most common grade 3 or worse adverse events were haematological toxicities in all 12 (100%) patients, including neutropenia (12 [100%]), anaemia (ten [83%]), and thrombocytopenia (ten [83%]). 11 (92%) patients had grade 1 or 2 cytokine release syndrome; no patients experienced immune effector cell-associated neurotoxicity syndrome. No treatment-related deaths were reported. Overall response at 1 month was observed in all 12 (100%) patients, with complete response in four (33%) patients, complete response with incomplete or partial haematological recovery in five (42%) patients, and morphological leukaemia-free state in three (25%) patients.INTERPRETATIONMETA 10-19 showed a manageable safety profile and promising antileukaemic activity in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia at low doses, highlighting that IL-10 engineering is a potential strategy for optimising CAR T-cell therapy in this patient group.FUNDINGCentre for Leading Medicine and Advanced Technologies of Institute of Health and Medicine, Hefei Comprehensive
{"title":"IL-10-expressing, anti-CD19 CAR T cells for patients with relapsed or refractory B-cell acute lymphoblastic leukaemia: an open-label, single-arm, phase 1 study.","authors":"Qianwen Xu,Yugang Guo,Min Gao,Lei Xue,Hui Xu,Hui Li,Xuhan Zhang,Chongling Liu,Youjia Li,Qian Chen,Jingjing Ren,Karthik Sathiyanadan,Yongxian Hu,Li Tang,He Huang,Xingbing Wang","doi":"10.1016/s2352-3026(25)00253-4","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00253-4","url":null,"abstract":"BACKGROUNDAlthough chimeric antigen receptor (CAR) T-cell therapy has improved clinical outcomes for patients with relapsed or refractory B-cell acute lymphoblastic leukaemia, treatment resistance and relapse after remission driven by CAR T-cell dysfunction remain significant clinical challenges. To mitigate this limitation, we developed anti-CD19 CAR T cells expressing IL-10 (META 10-19) and aimed to assess their safety and activity in this patient group.METHODSWe conducted an open-label, single-arm, phase 1 study at the First Affiliated Hospital of University of Science and Technology of China, Hefei, China. Patients aged 3-70 years with relapsed or refractory B-cell acute lymphoblastic leukaemia diagnosed according to the 5th edition of WHO's Classification of Haematolymphoid Tumours and an Eastern Cooperative Oncology Group performance status score of 0-1 were eligible for inclusion. Lymphodepletion was achieved by use of intravenous fludarabine (25-30 mg/m2 per day) and intravenous cyclophosphamide (250-300 mg/m2 per day) from day -5 to -3. META 10-19 was administered intravenously in a single infusion of 0·1 × 106 or 0·2 × 106 CAR T cells per kg. The primary endpoints were safety, assessed by dose-limiting toxicity, immune effector cell-associated toxicity, and other treatment-related adverse events; and activity, assessed by clinical response rate and survival. Safety and activity were analysed in all eligible patients who received META 10-19 infusion. This study is registered with ClinicalTrials.gov, NCT05747157, and has been completed.FINDINGSBetween May 16, 2023, and July 29, 2024, 15 patients were enrolled and underwent whole-blood collection. 12 patients (median age 48 years [IQR 33-53]) received META 10-19 infusion and were included in the analyses, of whom all patients were Chinese, seven (58%) were men, and five (42%) were women. Median follow-up was 12·5 months (IQR 7·4-15·6). The most common grade 3 or worse adverse events were haematological toxicities in all 12 (100%) patients, including neutropenia (12 [100%]), anaemia (ten [83%]), and thrombocytopenia (ten [83%]). 11 (92%) patients had grade 1 or 2 cytokine release syndrome; no patients experienced immune effector cell-associated neurotoxicity syndrome. No treatment-related deaths were reported. Overall response at 1 month was observed in all 12 (100%) patients, with complete response in four (33%) patients, complete response with incomplete or partial haematological recovery in five (42%) patients, and morphological leukaemia-free state in three (25%) patients.INTERPRETATIONMETA 10-19 showed a manageable safety profile and promising antileukaemic activity in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia at low doses, highlighting that IL-10 engineering is a potential strategy for optimising CAR T-cell therapy in this patient group.FUNDINGCentre for Leading Medicine and Advanced Technologies of Institute of Health and Medicine, Hefei Comprehensive ","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145319155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-16DOI: 10.1016/s2352-3026(25)00263-7
Rawan G Faramand,Lori Muffly
{"title":"Cytokine-engineered CAR T-cell therapy in relapsed or refractory B-cell acute lymphoblastic leukaemia.","authors":"Rawan G Faramand,Lori Muffly","doi":"10.1016/s2352-3026(25)00263-7","DOIUrl":"https://doi.org/10.1016/s2352-3026(25)00263-7","url":null,"abstract":"","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"134 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145319154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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