Pub Date : 2025-02-01DOI: 10.1016/S2352-3026(24)00350-8
Hege Kristin Gravdahl Garelius, Timothy Bagguley, Adele Taylor, Pierre Fenaux, David Bowen, Argiris Symeonidis, Moshe Mittelmann, Reinhard Stauder, Jaroslav Čermák, Guillermo Sanz, Saskia Langemeijer, Luca Malcovati, Ulrich Germing, Laurence Sanhes, Maud d'Aveni, Dominic Culligan, Ioannis Kotsianidis, Karin A Koinig, Corine van Marrewijk, Simon Crouch, Theo deWitte, Alexandra Smith, Eva Hellström-Lindberg
<p><strong>Background: </strong>In our previous study on erythropoiesis-stimulating agent (ESA) treatment in lower risk myelodysplastic syndromes from the European MDS (EUMDS) Registry, we showed that patients treated with ESAs had longer survival compared with patients who receive red blood cell transfusion (RBCT). In this study, with a longer follow up time and more patients included, we aimed to assess long-term effects on survival and health-related quality of life (HRQoL) of exposure to ESAs with or without RBCT in patients with lower risk myelodysplastic syndromes.</p><p><strong>Methods: </strong>The EUMDS Registry is a non-interventional, longitudinal, real-world registry prospectively enrolling newly diagnosed patients older than 18 years with lower risk (International Prognostic Scoring System low or intermediate-1) myelodysplastic syndromes from 16 European countries and Israel. The analysis was restricted to patients with haemoglobin concentrations less than 100 g/L enrolled between Jan 1, 2008, and July 1, 2019, with last censoring of data on Dec 31, 2021. Patient management was recorded every 6 months, including treatment, transfusions, and HRQoL. ESA treatment followed local guidelines. The patients were separated into four groups at each study visit: no ESA or RBCT, ESA only, ESA plus RBCT, and RBCT only. The data were analysed longitudinally over time according to ESA and RBCT status during each 6-month interval, using propensity score matching. The main outcomes were median overall survival and leukaemia-free survival, and HRQoL. This study is registered with ClinicalTrials.gov, NCT00600860, as is ongoing.</p><p><strong>Findings: </strong>2448 patients (the ESA-unexposed group [n=1265] and ESA-exposed group [n=1183]) were diagnosed before July 1, 2019; 1520 (62·1%) were male and 928 (37·9%) were female. Median follow-up time was 3·9 years (IQR 1·6-6·5). After applying eligibility criteria and propensity matching, there were 426 patients in the ESA-unexposed group and 744 patients in the ESA-exposed group. Median overall survival in the ESA exposed group was 44·9 months (95% CI 40·2-50·5) compared with 34·8 months (28·6-39·2) in the ESA unexposed group; the absolute difference was 10·1 months (95% CI 2·2-18·0; hazard ratio [HR] 0·70 [95% CI 0·59-0·83]; p<0·0001). Patients without RBCT in the presence or absence of ESA exposure maintained significantly better HRQoL than those with RBCT, irrespective of ESA exposure (linear mixed effect model of EQ-5d-3L index score, RBCT coefficient -0·04 [95% CI -0·06 to 0·03], p<0·0001; linear mixed effect model of VAS, -4·57 [-6·02 to -3·13], p<0·0001).</p><p><strong>Interpretation: </strong>ESA treatment in patients with lower risk myelodysplastic syndromes significantly improves overall survival when started before or early after the onset of regular transfusion therapy. Avoiding RBCT is associated with significantly better HRQoL.</p><p><strong>Funding: </strong>H2020 European Research Council
{"title":"Survival and quality of life in patients with lower risk myelodysplastic syndromes exposed to erythropoiesis-stimulating agents: an observational cohort study.","authors":"Hege Kristin Gravdahl Garelius, Timothy Bagguley, Adele Taylor, Pierre Fenaux, David Bowen, Argiris Symeonidis, Moshe Mittelmann, Reinhard Stauder, Jaroslav Čermák, Guillermo Sanz, Saskia Langemeijer, Luca Malcovati, Ulrich Germing, Laurence Sanhes, Maud d'Aveni, Dominic Culligan, Ioannis Kotsianidis, Karin A Koinig, Corine van Marrewijk, Simon Crouch, Theo deWitte, Alexandra Smith, Eva Hellström-Lindberg","doi":"10.1016/S2352-3026(24)00350-8","DOIUrl":"10.1016/S2352-3026(24)00350-8","url":null,"abstract":"<p><strong>Background: </strong>In our previous study on erythropoiesis-stimulating agent (ESA) treatment in lower risk myelodysplastic syndromes from the European MDS (EUMDS) Registry, we showed that patients treated with ESAs had longer survival compared with patients who receive red blood cell transfusion (RBCT). In this study, with a longer follow up time and more patients included, we aimed to assess long-term effects on survival and health-related quality of life (HRQoL) of exposure to ESAs with or without RBCT in patients with lower risk myelodysplastic syndromes.</p><p><strong>Methods: </strong>The EUMDS Registry is a non-interventional, longitudinal, real-world registry prospectively enrolling newly diagnosed patients older than 18 years with lower risk (International Prognostic Scoring System low or intermediate-1) myelodysplastic syndromes from 16 European countries and Israel. The analysis was restricted to patients with haemoglobin concentrations less than 100 g/L enrolled between Jan 1, 2008, and July 1, 2019, with last censoring of data on Dec 31, 2021. Patient management was recorded every 6 months, including treatment, transfusions, and HRQoL. ESA treatment followed local guidelines. The patients were separated into four groups at each study visit: no ESA or RBCT, ESA only, ESA plus RBCT, and RBCT only. The data were analysed longitudinally over time according to ESA and RBCT status during each 6-month interval, using propensity score matching. The main outcomes were median overall survival and leukaemia-free survival, and HRQoL. This study is registered with ClinicalTrials.gov, NCT00600860, as is ongoing.</p><p><strong>Findings: </strong>2448 patients (the ESA-unexposed group [n=1265] and ESA-exposed group [n=1183]) were diagnosed before July 1, 2019; 1520 (62·1%) were male and 928 (37·9%) were female. Median follow-up time was 3·9 years (IQR 1·6-6·5). After applying eligibility criteria and propensity matching, there were 426 patients in the ESA-unexposed group and 744 patients in the ESA-exposed group. Median overall survival in the ESA exposed group was 44·9 months (95% CI 40·2-50·5) compared with 34·8 months (28·6-39·2) in the ESA unexposed group; the absolute difference was 10·1 months (95% CI 2·2-18·0; hazard ratio [HR] 0·70 [95% CI 0·59-0·83]; p<0·0001). Patients without RBCT in the presence or absence of ESA exposure maintained significantly better HRQoL than those with RBCT, irrespective of ESA exposure (linear mixed effect model of EQ-5d-3L index score, RBCT coefficient -0·04 [95% CI -0·06 to 0·03], p<0·0001; linear mixed effect model of VAS, -4·57 [-6·02 to -3·13], p<0·0001).</p><p><strong>Interpretation: </strong>ESA treatment in patients with lower risk myelodysplastic syndromes significantly improves overall survival when started before or early after the onset of regular transfusion therapy. Avoiding RBCT is associated with significantly better HRQoL.</p><p><strong>Funding: </strong>H2020 European Research Council","PeriodicalId":48726,"journal":{"name":"Lancet Haematology","volume":"12 2","pages":"e128-e137"},"PeriodicalIF":15.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/S2352-3026(24)00351-X
Vincent Ribrag, Dominique Bron, Grzegorz Rymkiewicz, Dieter Hoelzer, Judit Jørgensen, Aythami de Armas-Castellano, Maria Trujillo-Martín, Pierre Fenaux, Luca Malcovati, Natacha Bolaños, Josep-Maria Ribera, Charles Herbaux, Clémentine Sarkozy, Pier Luigi Zinzani, Jan Walewski, Martine E D Chamuleau
Burkitt lymphoma is a rare lymphoma entity that represents less than 5% of adult lymphomas. Although prognosis has improved with dose-dense therapy, Burkitt lymphoma remains an area of clinical and biological research with specificities due to the high incidence of CNS involvement and tumour lysis syndrome in patients with a high tumour burden. Few consensus recommendations are available concerning diagnosis, treatment, and prognostic factors in adult patients. In this Review, a European Reference Network on Rare Haematological Diseases (ERN-EuroBloodNet) expert panel has reviewed recent advances in the management of Burkitt lymphoma in the first-line setting to develop updated evidence-based and expert opinion-based recommendations on the management of this disease. The expert panel consisted of ten clinicians and pathologists involved in the clinical management of Burkitt lymphoma from eight EU member states. Additionally, two haematologists were included to support the systematic review process. A balanced representation was ensured between individuals affiliated and not affiliated with ERN-EuroBloodNet. Together with providing current indications on diagnosis and risk-adapted first-line therapy, the Review contains specific recommendations for the identification and management of important complications of Burkitt lymphoma such as tumour lysis syndrome and CNS-oriented therapy, and recommendations for prognostic assessment to guide treatment. Finally, unresolved questions for Burkitt lymphoma are highlighted, including questions around genetics, imaging, and second-line therapies, along with patient perspective.
{"title":"Diagnosis and treatment of Burkitt lymphoma in adults: clinical practice guidelines from ERN-EuroBloodNet.","authors":"Vincent Ribrag, Dominique Bron, Grzegorz Rymkiewicz, Dieter Hoelzer, Judit Jørgensen, Aythami de Armas-Castellano, Maria Trujillo-Martín, Pierre Fenaux, Luca Malcovati, Natacha Bolaños, Josep-Maria Ribera, Charles Herbaux, Clémentine Sarkozy, Pier Luigi Zinzani, Jan Walewski, Martine E D Chamuleau","doi":"10.1016/S2352-3026(24)00351-X","DOIUrl":"https://doi.org/10.1016/S2352-3026(24)00351-X","url":null,"abstract":"<p><p>Burkitt lymphoma is a rare lymphoma entity that represents less than 5% of adult lymphomas. Although prognosis has improved with dose-dense therapy, Burkitt lymphoma remains an area of clinical and biological research with specificities due to the high incidence of CNS involvement and tumour lysis syndrome in patients with a high tumour burden. Few consensus recommendations are available concerning diagnosis, treatment, and prognostic factors in adult patients. In this Review, a European Reference Network on Rare Haematological Diseases (ERN-EuroBloodNet) expert panel has reviewed recent advances in the management of Burkitt lymphoma in the first-line setting to develop updated evidence-based and expert opinion-based recommendations on the management of this disease. The expert panel consisted of ten clinicians and pathologists involved in the clinical management of Burkitt lymphoma from eight EU member states. Additionally, two haematologists were included to support the systematic review process. A balanced representation was ensured between individuals affiliated and not affiliated with ERN-EuroBloodNet. Together with providing current indications on diagnosis and risk-adapted first-line therapy, the Review contains specific recommendations for the identification and management of important complications of Burkitt lymphoma such as tumour lysis syndrome and CNS-oriented therapy, and recommendations for prognostic assessment to guide treatment. Finally, unresolved questions for Burkitt lymphoma are highlighted, including questions around genetics, imaging, and second-line therapies, along with patient perspective.</p>","PeriodicalId":48726,"journal":{"name":"Lancet Haematology","volume":"12 2","pages":"e138-e150"},"PeriodicalIF":15.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2025-01-09DOI: 10.1016/S2352-3026(24)00344-2
Xin Zhao, Jing Sun, Zhihua Zhang, Miao Chen, Tiejun Gong, Guangsheng He, Yingmei Li, Hong Liu, Fei Li, Xin Li, Hu Zhou, Xiaoqin Wang, Mei Hong, Lei Lei, Hongyan Yin, Xian Luo, Yang Li, Songhua Fan, Xiaojun Guo, Michael M Shi, Weiguo Su, Liansheng Zhang, Bing Han, Fengkui Zhang
<p><strong>Background: </strong>Spleen tyrosine kinase inhibitors are potential treatment options for warm autoimmune haemolytic anaemia. This study aimed to assess the preliminary efficacy and safety of sovleplenib-an oral spleen tyrosine kinase inhibitor-in patients with warm autoimmune haemolytic anaemia in China. Here we report on the phase 2 results.</p><p><strong>Methods: </strong>This randomised, double-blind, placebo-controlled, phase 2 part from the phase 2/3 study was conducted at 13 centres in China. Eligible patients, aged 18-75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of no more than 2, had primary or secondary warm autoimmune haemolytic anaemia (stable underlying disease not requiring drug intervention) with no response to previous glucocorticoid treatment, haemoglobin of less than 100 g/L with active haemolysis, and a positive direct antiglobulin test. The study comprised two periods; patients were randomly assigned (3:1) to receive sovleplenib or placebo at 300 mg orally once a day in the 8-week double-blind period. Upon completion, all patients entered an open-label treatment period for at least 16 weeks and received sovleplenib 300 mg once a day until 24 weeks after the last patient was randomly assigned. The primary endpoint for phase 2 of the trial was overall haemoglobin response rate (haemoglobin ≥100 g/L with an increase of ≥20 g/L from baseline at least once, and haemoglobin not affected by rescue therapy, such as red blood cell transfusions, intravenous immunoglobulin, and glucocorticoids) by week 24. Efficacy analyses in the 0-8 week double-blind period included all patients who were randomly assigned, analysed by intention-to-treat. Safety analysis in the double-blind period included patients in the intention-to-treat population who received at least one dose of the study medication. This phase 2/3 study is registered with ClinicalTrials.gov, NCT05535933, and the phase 3 part is ongoing.</p><p><strong>Findings: </strong>Between Sept 26, 2022, and May 9, 2023, 34 patients were screened and 21 patients (four [19%] male and 17 [81%] female) were enrolled in the study and randomly assigned to receive either sovleplenib (n=16) or placebo (n=5). All 21 patients completed the 0-8-week double-blind treatment and entered the open-label treatment period. The overall haemoglobin response rate was 67% (14 of 21 patients) by week 24, and durable haemoglobin response rate was 48% (ten of 21 patients) by week 24. During the 0-8-week double-blind treatment, 13 (81%) of 16 patients in the sovleplenib group versus five (100%) of five patients taking placebo reported treatment-emergent adverse events (TEAEs), and four (25%) of 16 patients versus four (80%) of five patients reported grade 3 adverse events. Although all 21 patients had a TEAE during the 24-week treatment with sovleplenib, only seven (33%) patients had grade 3 events. The most common grade 3 TEAE was anaemia (four [19%] patients), which was
{"title":"Sovleplenib in patients with primary or secondary warm autoimmune haemolytic anaemia: results from phase 2 of a randomised, double-blind, placebo-controlled, phase 2/3 study.","authors":"Xin Zhao, Jing Sun, Zhihua Zhang, Miao Chen, Tiejun Gong, Guangsheng He, Yingmei Li, Hong Liu, Fei Li, Xin Li, Hu Zhou, Xiaoqin Wang, Mei Hong, Lei Lei, Hongyan Yin, Xian Luo, Yang Li, Songhua Fan, Xiaojun Guo, Michael M Shi, Weiguo Su, Liansheng Zhang, Bing Han, Fengkui Zhang","doi":"10.1016/S2352-3026(24)00344-2","DOIUrl":"10.1016/S2352-3026(24)00344-2","url":null,"abstract":"<p><strong>Background: </strong>Spleen tyrosine kinase inhibitors are potential treatment options for warm autoimmune haemolytic anaemia. This study aimed to assess the preliminary efficacy and safety of sovleplenib-an oral spleen tyrosine kinase inhibitor-in patients with warm autoimmune haemolytic anaemia in China. Here we report on the phase 2 results.</p><p><strong>Methods: </strong>This randomised, double-blind, placebo-controlled, phase 2 part from the phase 2/3 study was conducted at 13 centres in China. Eligible patients, aged 18-75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of no more than 2, had primary or secondary warm autoimmune haemolytic anaemia (stable underlying disease not requiring drug intervention) with no response to previous glucocorticoid treatment, haemoglobin of less than 100 g/L with active haemolysis, and a positive direct antiglobulin test. The study comprised two periods; patients were randomly assigned (3:1) to receive sovleplenib or placebo at 300 mg orally once a day in the 8-week double-blind period. Upon completion, all patients entered an open-label treatment period for at least 16 weeks and received sovleplenib 300 mg once a day until 24 weeks after the last patient was randomly assigned. The primary endpoint for phase 2 of the trial was overall haemoglobin response rate (haemoglobin ≥100 g/L with an increase of ≥20 g/L from baseline at least once, and haemoglobin not affected by rescue therapy, such as red blood cell transfusions, intravenous immunoglobulin, and glucocorticoids) by week 24. Efficacy analyses in the 0-8 week double-blind period included all patients who were randomly assigned, analysed by intention-to-treat. Safety analysis in the double-blind period included patients in the intention-to-treat population who received at least one dose of the study medication. This phase 2/3 study is registered with ClinicalTrials.gov, NCT05535933, and the phase 3 part is ongoing.</p><p><strong>Findings: </strong>Between Sept 26, 2022, and May 9, 2023, 34 patients were screened and 21 patients (four [19%] male and 17 [81%] female) were enrolled in the study and randomly assigned to receive either sovleplenib (n=16) or placebo (n=5). All 21 patients completed the 0-8-week double-blind treatment and entered the open-label treatment period. The overall haemoglobin response rate was 67% (14 of 21 patients) by week 24, and durable haemoglobin response rate was 48% (ten of 21 patients) by week 24. During the 0-8-week double-blind treatment, 13 (81%) of 16 patients in the sovleplenib group versus five (100%) of five patients taking placebo reported treatment-emergent adverse events (TEAEs), and four (25%) of 16 patients versus four (80%) of five patients reported grade 3 adverse events. Although all 21 patients had a TEAE during the 24-week treatment with sovleplenib, only seven (33%) patients had grade 3 events. The most common grade 3 TEAE was anaemia (four [19%] patients), which was","PeriodicalId":48726,"journal":{"name":"Lancet Haematology","volume":" ","pages":"e97-e108"},"PeriodicalIF":15.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/S2352-3026(24)00356-9
Tanya M Wildes
{"title":"Optimising quadruplet regimens to broaden eligibility in multiple myeloma.","authors":"Tanya M Wildes","doi":"10.1016/S2352-3026(24)00356-9","DOIUrl":"https://doi.org/10.1016/S2352-3026(24)00356-9","url":null,"abstract":"","PeriodicalId":48726,"journal":{"name":"Lancet Haematology","volume":"12 2","pages":"e87-e88"},"PeriodicalIF":15.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/S2352-3026(24)00380-6
Tony Kirby
{"title":"Oreofe Odejide-aiming to raise the bar in haematology care.","authors":"Tony Kirby","doi":"10.1016/S2352-3026(24)00380-6","DOIUrl":"https://doi.org/10.1016/S2352-3026(24)00380-6","url":null,"abstract":"","PeriodicalId":48726,"journal":{"name":"Lancet Haematology","volume":"12 1","pages":"e10"},"PeriodicalIF":15.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-11-04DOI: 10.1016/S2352-3026(24)00273-4
Giulia Agliardi, Juliana Dias, Alexandros Rampotas, John Garcia, Claire Roddie
Autologous chimeric antigen receptor (CAR) T-cell therapy has transformed the management of B-cell leukaemia and lymphoma. However, current manufacturing processes present logistical hurdles, restricting broader application. As clinical outcomes can be heavily influenced by the quality of autologous starting materials and production processes, strategies to improve product phenotype are crucial. Short manufacturing processes have the advantage of bringing products to patients more quickly and, in parallel, avoiding the highly differentiated and exhausted CAR T-cell phenotypes associated with prolonged ex vivo manufacture. This Review examines advances in our understanding of what constitutes an effective CAR T-cell product and approaches to improve product quality. Historically, strategies have relied on adjustments in medium composition and selection of less differentiated cell subtypes. Since 2020, the field has been shifting towards reduced-expansion protocols, no-activation protocols, and point-of-care manufacturing. These approaches have the advantage of a rapid turnaround while maintaining a less differentiated and exhausted phenotype. These efforts are leading to ultrarapid production methods and even elimination of ex vivo manipulation with the use of in vivo manufacturing approaches. In this Review, we focus on the advances needed to accelerate CAR T-cell manufacture (including near-patient methods), with an emphasis on improved therapeutic efficacy and rapid turnaround time, and simplified quality control procedures required to fully realise the clinical potential of CAR T-cell therapies.
自体嵌合抗原受体（CAR）T 细胞疗法改变了 B 细胞白血病和淋巴瘤的治疗方法。然而，目前的生产工艺存在物流障碍，限制了更广泛的应用。由于自体起始材料和生产工艺的质量会严重影响临床结果，因此改善产品表型的策略至关重要。短期生产流程的优势在于能更快地为患者提供产品，同时还能避免因长期体外生产而导致的高度分化和衰竭的 CAR T 细胞表型。本综述探讨了我们对有效 CAR T 细胞产品构成要素的理解进展以及提高产品质量的方法。一直以来，相关策略都依赖于调整培养基成分和选择分化程度较低的细胞亚型。自 2020 年以来，该领域已转向减少扩增方案、无活化方案和护理点生产。这些方法的优点是周转快，同时保持分化程度较低和衰竭的表型。这些努力正在促成超快速生产方法，甚至通过使用体内生产方法消除体外操作。在这篇综述中，我们将重点关注加速 CAR T 细胞生产（包括接近患者的方法）所需的进步，重点是提高疗效、缩短周转时间以及简化质量控制程序，这些都是充分发挥 CAR T 细胞疗法临床潜力所必需的。
{"title":"Accelerating and optimising CAR T-cell manufacture to deliver better patient products.","authors":"Giulia Agliardi, Juliana Dias, Alexandros Rampotas, John Garcia, Claire Roddie","doi":"10.1016/S2352-3026(24)00273-4","DOIUrl":"10.1016/S2352-3026(24)00273-4","url":null,"abstract":"<p><p>Autologous chimeric antigen receptor (CAR) T-cell therapy has transformed the management of B-cell leukaemia and lymphoma. However, current manufacturing processes present logistical hurdles, restricting broader application. As clinical outcomes can be heavily influenced by the quality of autologous starting materials and production processes, strategies to improve product phenotype are crucial. Short manufacturing processes have the advantage of bringing products to patients more quickly and, in parallel, avoiding the highly differentiated and exhausted CAR T-cell phenotypes associated with prolonged ex vivo manufacture. This Review examines advances in our understanding of what constitutes an effective CAR T-cell product and approaches to improve product quality. Historically, strategies have relied on adjustments in medium composition and selection of less differentiated cell subtypes. Since 2020, the field has been shifting towards reduced-expansion protocols, no-activation protocols, and point-of-care manufacturing. These approaches have the advantage of a rapid turnaround while maintaining a less differentiated and exhausted phenotype. These efforts are leading to ultrarapid production methods and even elimination of ex vivo manipulation with the use of in vivo manufacturing approaches. In this Review, we focus on the advances needed to accelerate CAR T-cell manufacture (including near-patient methods), with an emphasis on improved therapeutic efficacy and rapid turnaround time, and simplified quality control procedures required to fully realise the clinical potential of CAR T-cell therapies.</p>","PeriodicalId":48726,"journal":{"name":"Lancet Haematology","volume":" ","pages":"e57-e67"},"PeriodicalIF":15.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-12-04DOI: 10.1016/S2352-3026(24)00319-3
Modupe Idowu, Lucas Otieno, Bogdan Dumitriu, Clarisse L C Lobo, Swee Lay Thein, Biree Andemariam, Obiageli E Nnodu, Adlette Inati, Alexander K Glaros, Pablo Bartolucci, Raffaella Colombatti, Ali T Taher, Miguel R Abboud, Deepika Darbari, Kenneth I Ataga, Ali Bülent Antmen, Kevin H M Kuo, Samuel de Souza Medina, Abdulafeez Oluyadi, Varsha Iyer, Susan Morris, Amber M Yates, Hui Shao, Spurthi Patil, Rolandas Urbstonaitis, Ahmar U Zaidi, Sarah Gheuens, Wally R Smith
<p><strong>Background: </strong>Sickle cell disease, a debilitating, inherited haemolytic anaemia with premature morbidity and mortality, affects millions globally. Mitapivat, a first-in-class, oral, allosteric activator of pyruvate kinase, improves red blood cell survival by increasing ATP and diminishes sickling by decreasing 2,3-diphosphoglycerate. We aimed to evaluate the efficacy and safety of mitapivat in patients with sickle cell disease.</p><p><strong>Methods: </strong>We report results from the phase 2, 12-week, double-blind period of RISE UP, a global, phase 2/3, double-blind, randomised, placebo-controlled trial. The phase 2 part of the study was conducted at 32 clinical study sites across 13 countries. Patients aged 16 years or older with a confirmed diagnosis of sickle cell disease (any genotype), baseline haemoglobin of 5·5-10·5 g/dL (inclusive), and two to ten sickle cell pain crises within 12 months before providing informed consent, were randomly assigned 1:1:1 to receive oral mitapivat 50 mg, 100 mg, or placebo twice daily, in this portion of the study which is now complete. Randomisation was performed using a permuted-block method and concealed with an interactive response system; patients, investigators, and individuals assessing outcomes were masked to treatment assignment. Primary efficacy and safety endpoints were haemoglobin response (≥1·0 g/dL increase from baseline in average haemoglobin concentration from week 10 through week 12), and type, severity, and relationship to study drug of adverse and serious adverse events. Efficacy and safety endpoints were evaluated in the full analysis set (all randomly assigned patients) and safety analysis set (all patients who received at least one dose of study drug), respectively. This study is registered with ClinicalTrials.gov as part of an ongoing phase 2/3 study (NCT05031780).</p><p><strong>Findings: </strong>Between Jan 19, 2022, and April 25, 2023, 79 patients were randomly assigned (51 [65%] female, 28 [35%] male; 46 [58%] Black or African American, 26 [33%] White, five [6%] multiracial, two [3%] Asian); 26 received mitapivat 50 mg, 26 received mitapivat 100 mg, and 27 received placebo, twice daily. Both treatment groups showed a statistically significant haemoglobin response rate versus placebo (12 [46%] of 26 patients in the mitapivat 50 mg group and 13 [50%] of 26 patients in the mitapivat 100 mg group, versus one [4%] of 27 patients in the placebo group; two-sided p=0·0003 and p=0·0001, respectively). Mitapivat was generally well tolerated. Serious adverse events were reported in two (8%) of 26 patients in the mitapivat 50 mg group, four (15%) of 26 patients in the mitapivat 100 mg group, and three (11%) of 27 patients in the placebo group; grade 3 or worse adverse events occurred in three (12%), five (19%), and two (7%) patients, respectively. No serious or grade 3 or worse adverse events were considered treatment related and there were no treatment-related deaths. The mo
{"title":"Safety and efficacy of mitapivat in sickle cell disease (RISE UP): results from the phase 2 portion of a global, double-blind, randomised, placebo-controlled trial.","authors":"Modupe Idowu, Lucas Otieno, Bogdan Dumitriu, Clarisse L C Lobo, Swee Lay Thein, Biree Andemariam, Obiageli E Nnodu, Adlette Inati, Alexander K Glaros, Pablo Bartolucci, Raffaella Colombatti, Ali T Taher, Miguel R Abboud, Deepika Darbari, Kenneth I Ataga, Ali Bülent Antmen, Kevin H M Kuo, Samuel de Souza Medina, Abdulafeez Oluyadi, Varsha Iyer, Susan Morris, Amber M Yates, Hui Shao, Spurthi Patil, Rolandas Urbstonaitis, Ahmar U Zaidi, Sarah Gheuens, Wally R Smith","doi":"10.1016/S2352-3026(24)00319-3","DOIUrl":"10.1016/S2352-3026(24)00319-3","url":null,"abstract":"<p><strong>Background: </strong>Sickle cell disease, a debilitating, inherited haemolytic anaemia with premature morbidity and mortality, affects millions globally. Mitapivat, a first-in-class, oral, allosteric activator of pyruvate kinase, improves red blood cell survival by increasing ATP and diminishes sickling by decreasing 2,3-diphosphoglycerate. We aimed to evaluate the efficacy and safety of mitapivat in patients with sickle cell disease.</p><p><strong>Methods: </strong>We report results from the phase 2, 12-week, double-blind period of RISE UP, a global, phase 2/3, double-blind, randomised, placebo-controlled trial. The phase 2 part of the study was conducted at 32 clinical study sites across 13 countries. Patients aged 16 years or older with a confirmed diagnosis of sickle cell disease (any genotype), baseline haemoglobin of 5·5-10·5 g/dL (inclusive), and two to ten sickle cell pain crises within 12 months before providing informed consent, were randomly assigned 1:1:1 to receive oral mitapivat 50 mg, 100 mg, or placebo twice daily, in this portion of the study which is now complete. Randomisation was performed using a permuted-block method and concealed with an interactive response system; patients, investigators, and individuals assessing outcomes were masked to treatment assignment. Primary efficacy and safety endpoints were haemoglobin response (≥1·0 g/dL increase from baseline in average haemoglobin concentration from week 10 through week 12), and type, severity, and relationship to study drug of adverse and serious adverse events. Efficacy and safety endpoints were evaluated in the full analysis set (all randomly assigned patients) and safety analysis set (all patients who received at least one dose of study drug), respectively. This study is registered with ClinicalTrials.gov as part of an ongoing phase 2/3 study (NCT05031780).</p><p><strong>Findings: </strong>Between Jan 19, 2022, and April 25, 2023, 79 patients were randomly assigned (51 [65%] female, 28 [35%] male; 46 [58%] Black or African American, 26 [33%] White, five [6%] multiracial, two [3%] Asian); 26 received mitapivat 50 mg, 26 received mitapivat 100 mg, and 27 received placebo, twice daily. Both treatment groups showed a statistically significant haemoglobin response rate versus placebo (12 [46%] of 26 patients in the mitapivat 50 mg group and 13 [50%] of 26 patients in the mitapivat 100 mg group, versus one [4%] of 27 patients in the placebo group; two-sided p=0·0003 and p=0·0001, respectively). Mitapivat was generally well tolerated. Serious adverse events were reported in two (8%) of 26 patients in the mitapivat 50 mg group, four (15%) of 26 patients in the mitapivat 100 mg group, and three (11%) of 27 patients in the placebo group; grade 3 or worse adverse events occurred in three (12%), five (19%), and two (7%) patients, respectively. No serious or grade 3 or worse adverse events were considered treatment related and there were no treatment-related deaths. The mo","PeriodicalId":48726,"journal":{"name":"Lancet Haematology","volume":" ","pages":"e35-e44"},"PeriodicalIF":15.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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