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Bortezomib before and after high-dose therapy in transplant-eligible patients with newly diagnosed multiple myeloma: Long-term overall survival after more than 10 years of follow-up from the phase III HOVON-65/GMMG-HD4 trial 对符合移植条件的新诊断多发性骨髓瘤患者进行大剂量治疗前后的硼替佐米治疗:HOVON-65/GMMG-HD4 III期试验10多年随访后的长期总生存率
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-20 DOI: 10.1002/hem3.70052
Elias K. Mai, Axel Nogai, Henk M. Lokhorst, Bronno van der Holt, Sonja Zweegman, Katja C. Weisel, Sandra Croockewit, Anna Jauch, Jens Hillengass, Marian Stevens-Kroef, Marc S. Raab, Annemiek Broijl, Gerard M. J. Bos, Peter Brossart, Paula Ypma, Christine Hanoun, Uta Bertsch, Thomas Hielscher, Hans J. Salwender, Christoph Scheid, Hartmut Goldschmidt, Pieter Sonneveld
<p>Life expectancy in patients with multiple myeloma (MM) has increased due to the availability of effective drugs such as proteasome inhibitors (PIs),<span><sup>1, 2</sup></span> immunomodulatory drugs (IMiDs),<span><sup>3-5</sup></span> and more recently, monoclonal antibodies.<span><sup>6-8</sup></span></p><p>While the progression-free survival (PFS) rates and the depth of response increase with the use of modern multi-drug combinations, it is not clear whether these effects will translate into an improved long-term overall survival (OS). To draw such conclusions, long-term follow-up analyses from trials are needed as comparators for future trials. Here, we report on the long-term overall survival of the HOVON-65/GMMG-HD4 trial including the OS after more than 10 years, and the role of established prognostic factors.</p><p>The investigator-sponsored, open-label, randomized HOVON-65/GMMG-HD4 phase III trial was conducted by the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) and the German-speaking Myeloma Multicenter Group (GMMG) in 75 centers in the Netherlands, Belgium, and Germany from May 2005 to May 2008 and included 827 eligible patients. The trial was registered at www.trialregister.nl (until June 2022) and https://trialsearch.who.int/ as NTR213, at www.isrctn.com as ISRCTN64455289 and at www.clinicaltrialsregister.eu as EudraCT2004-000944-26. The ethics committees of the Erasmus University Medical Center, the University of Heidelberg, and all participating sites approved this trial. All patients gave written informed consent. The study was conducted in accordance with the European Clinical Trial Directive (2005) and the Declaration of Helsinki (1996).</p><p>Initial results of the trial have been published and include a detailed study protocol, inclusion and exclusion criteria, randomization procedures and toxicities,<span><sup>9</sup></span> and results after a median follow-up of 96 months.<span><sup>10</sup></span> After that, only OS data were collected on which we here report the final long-term survival data.</p><p>The aim of the trial was to investigate the use of bortezomib (BTZ) in induction and maintenance compared to treatment with classical cytotoxic agents as induction and thalidomide maintenance in transplant-eligible patients regarding the primary endpoint PFS, while OS was a secondary endpoint. Patients were randomized 1:1 to receive either vincristine, adriamycin, and dexamethasone (VAD) as induction therapy, followed by high-dose chemotherapy with melphalan and autologous stem-cell transplantation (ASCT), followed by maintenance therapy with thalidomide (VAD arm). In the PAD arm, BTZ, adriamycin, and dexamethasone were used in induction, followed by ASCT and maintenance with BTZ. Patients were stratified by center and International Staging System (ISS, I vs. II vs. III). A single ASCT was planned in the HOVON group, whereas in the GMMG, a tandem ASCT was planned. Patients with an HLA-identical sib
10 在 827 名患者中,508 人(61%)死亡,78 人(9%)失去随访机会。包括失去随访的患者在内,319 名仍存活的患者的中位随访时间为 11.4 年(四分位数间距:10.2-12.3)。VAD治疗组的12年OS为32%(95% CI:27%-37%),而PAD治疗组为36%(95% CI:31%-41%)(图1A和佐证资料附录第6页)。无论是 Cox 回归分析(HR = 0.87,95% CI:0.73-1.04,p = 0.12,根据 ISS 调整)还是分层对数秩检验(p = 0.15),OS 的差异均无统计学意义。单变量分析以森林图的形式显示在图 1B 中。与之前的报告9、10 一样,ISS 3 期(HR = 0.66,95% CI:0.45-0.97)、del(13q14)(HR = 0.68,95% CI:0.51-0.90)和肾功能损伤(HR = 0.31,95% CI:0.16-0.57)患者亚组显示,PAD 与 VAD 治疗相比,患者有望获益。为了进一步评估选定基线特征对 OS 的预后价值,我们进行了多变量 Cox 回归分析(表 1)。肾功能受损、细胞遗传学不良(仅 GMMG 患者10)患者的 OS,以及根据之前分析的反应状态得出的 OS,见佐证资料 S1:图 1-3,与之前试验的长期随访相比保持不变10。然而,研究组之间的程序有所不同,尤其是在前期异基因移植、串联 ASCT 的使用以及维持治疗的持续时间方面。对自最后一次 ASCT 日期起的 OS 进行的事后分析显示,41%(95% CI:36%-45%)的单次 ASCT 患者和 41%(95% CI:34%-47%)的串联 ASCT 患者的 10 年 OS(HR = 0.99,95% CI:0.81-1.21,P = 0.93)。多中心III期试验HOVON-65/GMMG-HD4的最终长期随访中位数为11.4年,超过35%的患者存活,总体意向治疗人群的10年OS为40%(95% CI:36%-43%)。在单变量分析中,各研究臂的OS差异不大,但在多变量分析中,PAD研究臂的OS优势明显。在肾功能受损的患者中,与 VAD 相比,PAD 的 OS 显著改善,与无肾功能受损的患者相比,OS 相似。同样,PAD 治疗组也克服了 del(17p13) 对预后的负面影响,10 年的 OS 显著提高了 37%,而无 del(17p13) 患者的 OS 为 43%。尽管将化疗加沙利度胺的策略与硼替佐米的策略进行了比较,但在 OS 方面的差异相当小。在复发性 MM 中使用新型疗法可能会部分克服一线疗法疗效较差的问题。与 PAD 组相比,VAD 组首次复发患者使用硼替佐米的比例确实更高(60% 对 33%)10。由于早期复发的患者通常具有高危特征,而在复发时这些新型、更有效的药物可能尚未上市,这可能在一定程度上解释了我们的 OS 结果,尤其是在高危 MM 患者中,并支持对具有高危特征的患者采用更强烈的诱导治疗的风险适应策略。然而,在有 del(17p13) 或肾功能损害的亚组患者中,观察到了 OS 的改善。此外,相当一部分患者存活了 12 年甚至更长时间,这表明目前的 MM 治疗策略是有效的,并强调了在未来试验中进行长期随访分析的重要性。
{"title":"Bortezomib before and after high-dose therapy in transplant-eligible patients with newly diagnosed multiple myeloma: Long-term overall survival after more than 10 years of follow-up from the phase III HOVON-65/GMMG-HD4 trial","authors":"Elias K. Mai,&nbsp;Axel Nogai,&nbsp;Henk M. Lokhorst,&nbsp;Bronno van der Holt,&nbsp;Sonja Zweegman,&nbsp;Katja C. Weisel,&nbsp;Sandra Croockewit,&nbsp;Anna Jauch,&nbsp;Jens Hillengass,&nbsp;Marian Stevens-Kroef,&nbsp;Marc S. Raab,&nbsp;Annemiek Broijl,&nbsp;Gerard M. J. Bos,&nbsp;Peter Brossart,&nbsp;Paula Ypma,&nbsp;Christine Hanoun,&nbsp;Uta Bertsch,&nbsp;Thomas Hielscher,&nbsp;Hans J. Salwender,&nbsp;Christoph Scheid,&nbsp;Hartmut Goldschmidt,&nbsp;Pieter Sonneveld","doi":"10.1002/hem3.70052","DOIUrl":"https://doi.org/10.1002/hem3.70052","url":null,"abstract":"&lt;p&gt;Life expectancy in patients with multiple myeloma (MM) has increased due to the availability of effective drugs such as proteasome inhibitors (PIs),&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; immunomodulatory drugs (IMiDs),&lt;span&gt;&lt;sup&gt;3-5&lt;/sup&gt;&lt;/span&gt; and more recently, monoclonal antibodies.&lt;span&gt;&lt;sup&gt;6-8&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;While the progression-free survival (PFS) rates and the depth of response increase with the use of modern multi-drug combinations, it is not clear whether these effects will translate into an improved long-term overall survival (OS). To draw such conclusions, long-term follow-up analyses from trials are needed as comparators for future trials. Here, we report on the long-term overall survival of the HOVON-65/GMMG-HD4 trial including the OS after more than 10 years, and the role of established prognostic factors.&lt;/p&gt;&lt;p&gt;The investigator-sponsored, open-label, randomized HOVON-65/GMMG-HD4 phase III trial was conducted by the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) and the German-speaking Myeloma Multicenter Group (GMMG) in 75 centers in the Netherlands, Belgium, and Germany from May 2005 to May 2008 and included 827 eligible patients. The trial was registered at www.trialregister.nl (until June 2022) and https://trialsearch.who.int/ as NTR213, at www.isrctn.com as ISRCTN64455289 and at www.clinicaltrialsregister.eu as EudraCT2004-000944-26. The ethics committees of the Erasmus University Medical Center, the University of Heidelberg, and all participating sites approved this trial. All patients gave written informed consent. The study was conducted in accordance with the European Clinical Trial Directive (2005) and the Declaration of Helsinki (1996).&lt;/p&gt;&lt;p&gt;Initial results of the trial have been published and include a detailed study protocol, inclusion and exclusion criteria, randomization procedures and toxicities,&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; and results after a median follow-up of 96 months.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; After that, only OS data were collected on which we here report the final long-term survival data.&lt;/p&gt;&lt;p&gt;The aim of the trial was to investigate the use of bortezomib (BTZ) in induction and maintenance compared to treatment with classical cytotoxic agents as induction and thalidomide maintenance in transplant-eligible patients regarding the primary endpoint PFS, while OS was a secondary endpoint. Patients were randomized 1:1 to receive either vincristine, adriamycin, and dexamethasone (VAD) as induction therapy, followed by high-dose chemotherapy with melphalan and autologous stem-cell transplantation (ASCT), followed by maintenance therapy with thalidomide (VAD arm). In the PAD arm, BTZ, adriamycin, and dexamethasone were used in induction, followed by ASCT and maintenance with BTZ. Patients were stratified by center and International Staging System (ISS, I vs. II vs. III). A single ASCT was planned in the HOVON group, whereas in the GMMG, a tandem ASCT was planned. Patients with an HLA-identical sib","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The incidence and clinical significance of monoclonal and oligoclonal protein bands in multiple myeloma patients after BCMA–CAR-T cell therapy: A retrospective study based on LEGEND-2 BCMA-CAR-T 细胞治疗后多发性骨髓瘤患者单克隆和寡克隆蛋白带的发生率和临床意义:基于 LEGEND-2 的回顾性研究
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-19 DOI: 10.1002/hem3.70054
Rui Liu, Gongzhizi Gao, Hongli Chen, Ruijun Dong, Wanggang Zhang, Wanhong Zhao, Jie Liu, Jianli Wang, Bo Lei, Baiyan Wang, Jiali Liu, Xuezhu Xu, Zujie Lin, Ruoyu Yang, Yiwen Wang, Aili He, Fangxia Wang, Ju Bai

The emergence of abnormal protein bands (APBs), also known as oligoclonal protein bands, has been documented in patients with multiple myeloma (MM) post hematopoietic stem cell transplantation. However, the incidence rate and clinical significance of APBs remain contentious. Few studies have explored the occurrence and prognostic implications of APBs in patients with MM treated with B-cell maturation antigen (BCMA)–specific chimeric antigen receptor (CAR)-T therapy. In this retrospective study, we examined the frequency, isotypes, and duration of APBs, as well as their correlation with MM disease characteristics, treatment response, clinical outcomes, and immune signature in patients with relapsed/refractory MM who had received LCAR-B38M therapy at the Xi'an site of the phase 1 LEGEND-2 trial. Among 47 patients assessed, 23 (48.9%) developed APBs following CAR-T therapy, with IgG being the most common isotype. The median onset and duration of APBs post-CAR-T infusion were 3.6 and 5.8 months, respectively. Patients with APBs demonstrated significantly improved response to LCAR-B38M therapy, along with longer overall and progression-free survival. Furthermore, those with APBs exhibited enhanced recovery rates of immunoglobulins and higher absolute counts of white blood cells, neutrophils, and lymphocytes post-CAR-T treatment compared to those without APBs. However, no significant differences were observed between the two groups in the percentages of various T-cell subsets and natural killer cells. Overall, the presence of APBs in patients with MM following CAR-T treatment was associated with deeper remission and a more favorable prognosis, suggesting a robust humoral response and subsequent immune reconstitution.

在造血干细胞移植后的多发性骨髓瘤(MM)患者中出现异常蛋白带(APBs),也称为寡克隆蛋白带,已有文献记载。然而,APBs的发病率和临床意义仍存在争议。很少有研究探讨了接受B细胞成熟抗原(BCMA)特异性嵌合抗原受体(CAR)-T疗法的多发性骨髓瘤患者中APB的发生率和预后意义。在这项回顾性研究中,我们研究了在LEGEND-2一期试验西安站接受LCAR-B38M治疗的复发/难治性MM患者中,APB的频率、同种型、持续时间及其与MM疾病特征、治疗反应、临床结果和免疫特征的相关性。在接受评估的47名患者中,23人(48.9%)在接受CAR-T治疗后出现了APB,IgG是最常见的同种型。输注 CAR-T 后 APB 的中位发病时间和持续时间分别为 3.6 个月和 5.8 个月。APB患者对LCAR-B38M疗法的反应明显改善,总生存期和无进展生存期也更长。此外,与无 APB 的患者相比,有 APB 的患者在接受 LCAR-T 治疗后免疫球蛋白的恢复率更高,白细胞、中性粒细胞和淋巴细胞的绝对计数也更高。不过,在各种 T 细胞亚群和自然杀伤细胞的百分比方面,两组之间没有观察到明显差异。总的来说,接受 CAR-T 治疗的 MM 患者体内存在 APB 与缓解程度更深和预后更有利有关,这表明患者体内存在强大的体液反应和随后的免疫重建。
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引用次数: 0
Monoclonal gammopathy of undetermined significance with multiple paraproteins: A population-based screening study 意义未定的单克隆丙种球蛋白病伴有多种副蛋白:基于人群的筛查研究
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-19 DOI: 10.1002/hem3.70046
Sæmundur Rögnvaldsson, Jón Þ. Óskarsson, Sigrun Thorsteinsdóttir, Malin Hultcrantz, Robert Palmason, Ingigerdur S. Sverrisdottir, Elias Eythorsson, Thorir E. Long, Isleifur Olafsson, Ingunn Thorsteinsdottir, Brynjar Vidarsson, Pall T. Onundarson, Bjarni A. Agnarsson, Margret Sigurdardottir, Asbjorn Jonsson, Brian G. M. Durie, Stephen Harding, Ola Landgren, Thorvardur J. Love, Sigurdur Y. Kristinsson

Monoclonal gammopathy of undetermined significance (MGUS) is the precursor of multiple myeloma (MM) and related disorders. MGUS is characterized by asymptomatic paraproteinemia. In some cases, multiple paraproteins can be identified but the clinical implications of this phenomenon are poorly understood. In this study, we aim to inform the approach to this challenging MGUS subgroup by utilizing data from iStopMM, a population-based screening study and randomized trial of follow-up strategies. In total, 75,422 Icelanders over the age of 40 were screened for MGUS with 3389 (4.4%) having at least one paraprotein of whom 303 (9%) had multiple paraproteins. IgM paraproteins were more common in those with multiple paraproteins (49% vs. 27% of paraproteins, p < 0.001), and IgM and non-IgM paraproteins frequently co-occurred (60% of cases). Two-thirds of these participants were randomized to active follow-up where only 31% of multiple paraproteins were persistent. Paraprotein concentrations were mostly independent, and although progression events were few, the progression rate was similar between those with multiple paraproteins and a single paraprotein. In a next-generation flow cytometry (NGF) sub-study, two phenotypically distinct aberrant plasma cell populations could be identified in some with multiple paraproteins. The findings suggest that multiple paraproteins often reflect independent ongoing disease processes that should be monitored independently but otherwise treated similarly to other MGUS cases. Specifically, the findings highlight the need for independent monitoring of IgM and non-IgM paraproteins in these individuals. The study provides novel insights into the management of this understudied MGUS subset.

意义未定的单克隆丙种球蛋白病(MGUS)是多发性骨髓瘤(MM)和相关疾病的前兆。MGUS 的特征是无症状的副蛋白血症。在某些病例中,可以发现多种副蛋白,但对这种现象的临床意义却知之甚少。在本研究中,我们旨在利用基于人群的筛查研究和随访策略随机试验 iStopMM 的数据,为这一具有挑战性的 MGUS 亚群的治疗方法提供参考。共有75422名40岁以上的冰岛人接受了MGUS筛查,3389人(4.4%)至少有一种副蛋白,其中303人(9%)有多种副蛋白。在有多种副蛋白的患者中,IgM 副蛋白更为常见(49% 对 27%,p < 0.001),IgM 和非 IgM 副蛋白经常同时出现(60% 的病例)。这些参与者中有三分之二被随机纳入积极随访,其中只有 31% 的多重副蛋白持续存在。副蛋白浓度大多是独立的,虽然进展事件很少,但多副蛋白和单副蛋白患者的进展率相似。在一项下一代流式细胞术(NGF)子研究中,可以在一些有多种副蛋白的患者中发现两种表型截然不同的异常浆细胞群。研究结果表明,多副蛋白通常反映了独立的持续性疾病过程,应单独对其进行监测,但在其他方面的治疗应与其他 MGUS 病例类似。具体而言,研究结果强调了对这些患者的 IgM 和非 IgM 副蛋白进行独立监测的必要性。该研究为这一研究不足的 MGUS 亚群的管理提供了新的见解。
{"title":"Monoclonal gammopathy of undetermined significance with multiple paraproteins: A population-based screening study","authors":"Sæmundur Rögnvaldsson,&nbsp;Jón Þ. Óskarsson,&nbsp;Sigrun Thorsteinsdóttir,&nbsp;Malin Hultcrantz,&nbsp;Robert Palmason,&nbsp;Ingigerdur S. Sverrisdottir,&nbsp;Elias Eythorsson,&nbsp;Thorir E. Long,&nbsp;Isleifur Olafsson,&nbsp;Ingunn Thorsteinsdottir,&nbsp;Brynjar Vidarsson,&nbsp;Pall T. Onundarson,&nbsp;Bjarni A. Agnarsson,&nbsp;Margret Sigurdardottir,&nbsp;Asbjorn Jonsson,&nbsp;Brian G. M. Durie,&nbsp;Stephen Harding,&nbsp;Ola Landgren,&nbsp;Thorvardur J. Love,&nbsp;Sigurdur Y. Kristinsson","doi":"10.1002/hem3.70046","DOIUrl":"https://doi.org/10.1002/hem3.70046","url":null,"abstract":"<p>Monoclonal gammopathy of undetermined significance (MGUS) is the precursor of multiple myeloma (MM) and related disorders. MGUS is characterized by asymptomatic paraproteinemia. In some cases, multiple paraproteins can be identified but the clinical implications of this phenomenon are poorly understood. In this study, we aim to inform the approach to this challenging MGUS subgroup by utilizing data from iStopMM, a population-based screening study and randomized trial of follow-up strategies. In total, 75,422 Icelanders over the age of 40 were screened for MGUS with 3389 (4.4%) having at least one paraprotein of whom 303 (9%) had multiple paraproteins. IgM paraproteins were more common in those with multiple paraproteins (49% vs. 27% of paraproteins, <i>p</i> &lt; 0.001), and IgM and non-IgM paraproteins frequently co-occurred (60% of cases). Two-thirds of these participants were randomized to active follow-up where only 31% of multiple paraproteins were persistent. Paraprotein concentrations were mostly independent, and although progression events were few, the progression rate was similar between those with multiple paraproteins and a single paraprotein. In a next-generation flow cytometry (NGF) sub-study, two phenotypically distinct aberrant plasma cell populations could be identified in some with multiple paraproteins. The findings suggest that multiple paraproteins often reflect independent ongoing disease processes that should be monitored independently but otherwise treated similarly to other MGUS cases. Specifically, the findings highlight the need for independent monitoring of IgM and non-IgM paraproteins in these individuals. The study provides novel insights into the management of this understudied MGUS subset.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A single-chain variable fragment-based bispecific T-cell activating antibody against CD117 enables T-cell mediated lysis of acute myeloid leukemia and hematopoietic stem and progenitor cells 基于单链可变片段的 CD117 双特异性 T 细胞激活抗体可实现 T 细胞介导的急性髓性白血病及造血干细胞和祖细胞裂解
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-19 DOI: 10.1002/hem3.70055
Laura Volta, Renier Myburgh, Mara Hofstetter, Christian Koch, Jonathan D. Kiefer, Celeste Gobbi, Francesco Manfredi, Kathrin Zimmermann, Philipp Kaufmann, Serena Fazio, Christian Pellegrino, Norman F. Russkamp, Danielle Villars, Mattia Matasci, Monique Maurer, Jan Mueller, Florin Schneiter, Paul Büschl, Niclas Harrer, Jacqueline Mock, Stefan Balabanov, César Nombela-Arrieta, Timm Schroeder, Dario Neri, Markus G. Manz

Acute myeloid leukemia (AML) derives from hematopoietic stem and progenitor cells (HSPCs). To date, no AML-exclusive, non-HSPC-expressed cell-surface target molecules for AML selective immunotherapy have been identified. Therefore, to still apply surface-directed immunotherapy in this disease setting, time-limited combined immune-targeting of AML cells and healthy HSPCs, followed by hematopoietic stem cell transplantation (HSCT), might be a viable therapeutic approach. To explore this, we generated a recombinant single-chain variable fragment-based bispecific T-cell engaging and activating antibody directed against CD3 on T-cells and CD117, the surface receptor for stem cell factor, expressed by both AML cells and healthy HSPCs. Bispecific CD117xCD3 targeting induced lysis of CD117-positive healthy human HSPCs, AML cell lines and patient-derived AML blasts in the presence of T-cells at subnanomolar concentrations in vitro. Furthermore, in immunocompromised mice, engrafted with human CD117-expressing leukemia cells and human T-cells, the bispecific molecule efficiently prevented leukemia growth in vivo. Additionally, in immunodeficient mice transplanted with healthy human HSPCs, the molecule decreased the number of CD117-positive cells in vivo. Therefore, bispecific CD117xCD3 targeting might be developed clinically in order to reduce CD117-expressing leukemia cells and HSPCs prior to HSCT.

急性髓性白血病(AML)源自造血干细胞和祖细胞(HSPC)。迄今为止,还没有发现急性髓性白血病专属的、非 HSPC 表达的细胞表面靶分子可用于急性髓性白血病的选择性免疫疗法。因此,要想在这种疾病中继续应用表面定向免疫疗法,对AML细胞和健康的HSPCs进行有时间限制的联合免疫靶向治疗,然后进行造血干细胞移植(HSCT),可能是一种可行的治疗方法。为了探索这一点,我们生成了一种基于重组单链可变片段的双特异性T细胞吸引和激活抗体,该抗体针对T细胞上的CD3和CD117(AML细胞和健康HSPC均表达的干细胞因子表面受体)。双特异性 CD117xCD3 靶向诱导体外亚纳摩尔浓度的 CD117 阳性健康人类 HSPC、AML 细胞系和患者来源的 AML 囊肿在 T 细胞存在的情况下发生裂解。此外,在接种了人类 CD117 表达的白血病细胞和人类 T 细胞的免疫缺陷小鼠体内,这种双特异性分子能有效阻止白血病的生长。此外,在移植了健康人类 HSPCs 的免疫缺陷小鼠体内,该分子还能减少 CD117 阳性细胞的数量。因此,双特异性 CD117xCD3 靶向可用于临床开发,以便在造血干细胞移植前减少 CD117 表达的白血病细胞和 HSPC。
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引用次数: 0
IL-11—An aging-related cytokine with opportunities for regulating hematopoiesis IL-11--一种与衰老有关的细胞因子,可调节造血功能。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-19 DOI: 10.1002/hem3.70050
David G. Kent
<p>Cytokines have long been known as chemical messengers that act upon cells in the blood system to induce proliferation and response to disease. Studying them at scale in a tissue context has been challenging due to functional redundancy and pleiotropic effects, but they remain an area of active investigation for a wide range of groups, especially now that new approaches are emerging to studying cytokine signaling dynamics at the single molecule level.<span><sup>1-3</sup></span> This summer, a huge study on the proinflammatory cytokine Interleukin 11 (IL-11) emerged in <i>Nature</i> magazine from the group of Stuart Cook—the paper <i>Inhibition of IL-11 signaling extends mammalian healthspan and lifespan</i><span><sup>4</sup></span> dropped into the hyperactive aging research community and caused quite a stir.</p><p>The headline statement: “Genetic deletion of <i>Il11</i> extended the lives of mice of both sexes, by 24.9% on average” caught the research world's attention. This was impressively followed by a series of studies that involved treating mice with an anti-IL-11 antibody from middle age (75 weeks) until death where the researchers observed another impressive increase in lifespan (>20%), strongly suggesting that early life events do not irrevocably sentence an organism to an early death. Simple in design and elegant in execution, the study details the genetic and pharmacological modulation of aging in both sexes. This positions the paper as one of the few that demonstrates a clear extension of lifespan through the removal of a single gene—one of the earliest examples of which is the <i>daf-2</i> c.elegans mutants<span><sup>5</sup></span> that have an extended lifespan. The authors go on to detail a wide range of metabolic and pathway profiling and imply that the metabolic, proinflammatory, and profibrotic roles of IL-11 are the mechanistic drivers of aging through the ERK-mTORC1 and JAK/STAT signaling pathways. This also suggests that JAK inhibitors, metformin, rapamycin, and so forth might have antiaging and antifibrotic roles as well, but the authors note that some of these current therapies struggle with on- and off-target toxicities that an anti-IL-11 therapy might not have. Indeed, an early-stage clinical trial is already underway using anti-IL-11 for the treatment of fibro-inflammatory diseases.</p><p>IL-11 is no stranger to stem cell and hematopoiesis research. It is one of a handful of critical molecules that interact with the glycoprotein 130 (gp130) family for signal transduction, in the good company of leukemia inhibitory factor (LIF) and interleukin 6 (IL-6) among others. These molecules have long been studied in stem cell systems (e.g., LIF in mouse embryonic stem cells and ciliary neurotrophic factor [CNTF] in neural stem cells) and have also been among the key regulators of hematopoietic stem cell (HSC) self-renewal in the form of IL-6 and IL-11. Early studies highlighted IL-11's partnership with the stem cell factor (S
众所周知,细胞因子是作用于血液系统细胞的化学信使,可诱导细胞增殖并对疾病做出反应。由于功能冗余和多效应,在组织背景下大规模研究细胞因子具有挑战性,但它们仍然是众多研究小组积极研究的领域,尤其是现在出现了在单分子水平研究细胞因子信号动态的新方法。今年夏天,斯图尔特-库克(Stuart Cook)小组在《自然》杂志上发表了一篇关于促炎细胞因子白细胞介素 11(IL-11)的重要研究论文--《抑制 IL-11 信号传导可延长哺乳动物的健康寿命》(Inhibition of IL-11 signaling extends mammalian healthspan and lifespan4),这篇论文一经发表,就在亢奋的衰老研究界引起了不小的轰动:"Il11基因缺失可延长雌雄小鼠的寿命,平均延长24.9%"的标题引起了研究界的关注。随后进行的一系列研究令人印象深刻,这些研究涉及用抗IL-11抗体治疗中年(75周)至死亡的小鼠,在这些研究中,研究人员观察到小鼠的寿命再次显著延长(20%),这有力地表明,生命早期的事件并不会不可逆转地判处生物体早死。该研究设计简单,执行优雅,详细介绍了基因和药物对两性衰老的调节作用。这使这篇论文成为少数几篇通过移除单个基因明确延长寿命的论文之一--其中最早的例子是daf-2 c.elegans突变体5,它们的寿命得到了延长。作者接着详细介绍了一系列代谢和通路分析,并暗示 IL-11 的代谢、促炎和促坏死作用是通过 ERK-mTORC1 和 JAK/STAT 信号通路导致衰老的机理驱动因素。这也表明,JAK 抑制剂、二甲双胍、雷帕霉素等也可能具有抗衰老和抗纤维化的作用,但作者指出,目前的一些疗法存在靶上和脱靶毒性,而抗 IL-11 疗法可能没有这些毒性。事实上,利用抗IL-11治疗纤维炎症性疾病的早期临床试验已经在进行中。IL-11对干细胞和造血研究来说并不陌生。它是与糖蛋白130(gp130)家族相互作用进行信号转导的少数关键分子之一,与白血病抑制因子(LIF)和白细胞介素6(IL-6)等分子齐名。长期以来,人们一直在干细胞系统中研究这些分子(如小鼠胚胎干细胞中的LIF和神经干细胞中的睫状神经营养因子[CNTF]),IL-6和IL-11也是造血干细胞自我更新的关键调节因子之一。早期的研究强调了IL-11与干细胞因子(SCF)在维持造血干细胞扩增培养物自我更新方面的合作关系,6, 7 但同样,IL-11也被证明对Yamazaki及其同事所描述的最新的、性能更好的基于PVA的培养系统来说是不可或缺的,该系统使用血小板生成素(TPO)和SCF来实现造血干细胞扩增。然而,有趣的是,最近有研究表明,在小鼠和人体环境中,IL-11 本身可使造血干细胞在体外保持冬眠状态9,10 造血干细胞在没有物理龛位的情况下保持单细胞状态,与新鲜分离的造血干细胞相比,造血干细胞在移植试验中保持了全部功能潜能。从库克研究小组的新发现来看,现在研究 IL-11 信号在衰老造血干细胞中的关系变得至关重要--在造血干细胞衰老过程中,是什么阻断了这一关键调节因子,它又将如何影响克隆造血的获得、炎症细胞因子的积累或白血病的发展?也许,最值得考虑的一个方面是,冬眠培养的造血干细胞功能是完全可逆的,而库克的研究则将 IL-11 与不可逆转的衰老状态联系起来。了解血液系统的变化,更具体地说是造血干细胞的变化以及炎症引起的衰老变化,将是一件非常有趣的事情。从直接应用于人类的角度看,阻断单一分子可延长25%的寿命似乎好得不像真的,但每一点都有帮助,而且几乎肯定会有一些引人入胜的科学发现。
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引用次数: 0
Preclinical evaluation of the CD38-targeting engineered toxin body MT-0169 against multiple myeloma 针对多发性骨髓瘤的 CD38 靶向工程毒素体 MT-0169 的临床前评估。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-14 DOI: 10.1002/hem3.70039
Wassilis S. C. Bruins, Rosa Rentenaar, John Newcomb, Wenrou Zheng, Ruud W. J. Ruiter, Thomas Baardemans, Eric Poma, Chris Moore, Garrett L. Robinson, Anya Lublinsky, Yuhong Zhang, Sakeena Syed, Michael Milhollen, Ajeeta B. Dash, Niels W. C. J. van de Donk, Richard W. J. Groen, Sonja Zweegman, Tuna Mutis

Despite significant progress in the treatment of multiple myeloma (MM), relapsed/refractory patients urgently require more effective therapies. We here describe the discovery, mechanism of action, and preclinical anti-MM activity of engineered toxin body MT-0169, a next-generation immunotoxin comprising a CD38-specific antibody fragment linked to a de-immunized Shiga-like toxin A subunit (SLTA) payload. We show that specific binding of MT-0169 to CD38 on MM cell lines triggers rapid internalization of SLTA, causing cell death via irreversible ribosome inhibition, protein synthesis blockade, and caspase 3/7 activation. In co-culture experiments, bone marrow mesenchymal stromal cells did not induce drug resistance against MT-0169. In the preclinical setting, MT-0169 effectively lysed primary MM cells from newly diagnosed and heavily pretreated MM patients, including those refractory to daratumumab, with minimal toxicity against nonmalignant hematopoietic cells. MM cell lysis showed a significant correlation with their CD38 expression levels but not with cytogenetic risk, tumor load, or number of prior lines of therapy. Finally, MT-0169 showed efficient in vivo anti-MM activity in various mouse xenograft models, including one in which MM cells are grown in a humanized bone marrow-like niche. These findings support clinical investigation of MT-0169 in relapsed/refractory MM patients, including those refractory to CD38-targeting immunotherapies.

尽管多发性骨髓瘤(MM)的治疗取得了重大进展,但复发/难治患者迫切需要更有效的疗法。我们在本文中描述了工程毒素体MT-0169的发现、作用机制和临床前抗多发性骨髓瘤活性,MT-0169是一种下一代免疫毒素,由CD38特异性抗体片段与去免疫的志贺样毒素A亚基(SLTA)有效载荷连接而成。我们的研究表明,MT-0169 与 MM 细胞系上 CD38 的特异性结合会引发 SLTA 的快速内化,通过不可逆的核糖体抑制、蛋白质合成阻断和 caspase 3/7 激活导致细胞死亡。在共培养实验中,骨髓间充质基质细胞不会诱发对 MT-0169 的耐药性。在临床前研究中,MT-0169能有效裂解新诊断和重度预处理的MM患者(包括对达拉单抗难治的患者)的原发性MM细胞,对非恶性造血细胞的毒性极小。MM细胞的溶解与它们的CD38表达水平有显著相关性,但与细胞遗传风险、肿瘤负荷或之前的治疗次数无关。最后,MT-0169在各种小鼠异种移植模型中显示出高效的体内抗MM活性,其中包括MM细胞在人源化骨髓样龛中生长的模型。这些研究结果支持对复发/难治性 MM 患者(包括 CD38 靶向免疫疗法难治者)进行 MT-0169 临床研究。
{"title":"Preclinical evaluation of the CD38-targeting engineered toxin body MT-0169 against multiple myeloma","authors":"Wassilis S. C. Bruins,&nbsp;Rosa Rentenaar,&nbsp;John Newcomb,&nbsp;Wenrou Zheng,&nbsp;Ruud W. J. Ruiter,&nbsp;Thomas Baardemans,&nbsp;Eric Poma,&nbsp;Chris Moore,&nbsp;Garrett L. Robinson,&nbsp;Anya Lublinsky,&nbsp;Yuhong Zhang,&nbsp;Sakeena Syed,&nbsp;Michael Milhollen,&nbsp;Ajeeta B. Dash,&nbsp;Niels W. C. J. van de Donk,&nbsp;Richard W. J. Groen,&nbsp;Sonja Zweegman,&nbsp;Tuna Mutis","doi":"10.1002/hem3.70039","DOIUrl":"10.1002/hem3.70039","url":null,"abstract":"<p>Despite significant progress in the treatment of multiple myeloma (MM), relapsed/refractory patients urgently require more effective therapies. We here describe the discovery, mechanism of action, and preclinical anti-MM activity of engineered toxin body MT-0169, a next-generation immunotoxin comprising a CD38-specific antibody fragment linked to a de-immunized Shiga-like toxin A subunit (SLTA) payload. We show that specific binding of MT-0169 to CD38 on MM cell lines triggers rapid internalization of SLTA, causing cell death via irreversible ribosome inhibition, protein synthesis blockade, and caspase 3/7 activation. In co-culture experiments, bone marrow mesenchymal stromal cells did not induce drug resistance against MT-0169. In the preclinical setting, MT-0169 effectively lysed primary MM cells from newly diagnosed and heavily pretreated MM patients, including those refractory to daratumumab, with minimal toxicity against nonmalignant hematopoietic cells. MM cell lysis showed a significant correlation with their CD38 expression levels but not with cytogenetic risk, tumor load, or number of prior lines of therapy. Finally, MT-0169 showed efficient in vivo anti-MM activity in various mouse xenograft models, including one in which MM cells are grown in a humanized bone marrow-like niche. These findings support clinical investigation of MT-0169 in relapsed/refractory MM patients, including those refractory to CD38-targeting immunotherapies.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Results of the prospective EORTC Children Leukemia Group study 58081 in precursor B- and T-cell acute lymphoblastic leukemia 前瞻性 EORTC 儿童白血病小组 58081 研究 B 细胞和 T 细胞急性淋巴细胞白血病的结果。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-13 DOI: 10.1002/hem3.70025
Carine Domenech, Michal Kicinski, Barbara De Moerloose, Caroline Piette, Wadih A. Chahla, Laure Kornreich, Marlène Pasquet, Anne Uyttebroeck, Alexandre Theron, Marilyne Poirée, Chloé Arfeuille, Marleen Bakkus, Nathalie Grardel, Catherine Paillard, Claire Freycon, Frédéric Millot, Pauline Simon, Pierre Philippet, Claire Pluchart, Stefan Suciu, Pierre Rohrlich, Alina Ferster, Yves Bertrand, Hélène Cavé, for the Children's Leukemia Group (CLG) of the European Organization for Research and Treatment of Cancer (EORTC)

Here, we report the results of the prospective cohort study EORTC-CLG 58081 and compare them to the control arm of the randomized phase 3 trial EORTC-CLG 58951, on which treatment recommendations were built. In both studies, patients aged 1–18 years with BCR::ABL1 negative acute lymphoblastic leukemia of the B-lineage (B-ALL) or T-lineage (T-ALL) were treated using a BFM backbone without cranial irradiation. Similarly to the control arm of 58951, prednisolone (PRED) 60 mg/m2/day was used for induction therapy, but a few modifications were made. Dexamethasone (DXM) was used in average-risk 2 (AR2) T-ALL and B-ALL during induction, 10 and 6 mg/m2/day, respectively. Leucovorin rescue was delayed to 42 h instead of 36 h after initiation of high-dose methotrexate, and a postconsolidation MRD time point was added to stratify patients. Between 2011 and 2017, 835 patients were prospectively enrolled in the 58081 study. Overall, the 5-year event-free survival (EFS) was 84.8% versus 83.6% (hazard ratio [HR], 0.96 [95% confidence interval [CI]: 0.76–1.21]) for 58081 versus 58951 considered as a control group, respectively, 84.3% versus 84.9% (HR, 1.06 [99% CI: 0.75–1.49]) in B-ALL but 87.3% versus 76.6% (HR, 0.59 [99% CI: 0.28–1.24]) in T-ALL. The comparison between the two studies regarding EFS differed by risk group (p = 0.012). The HR was 2.15 (99% CI: 0.67–6.85) for very low-risk but 0.34 (99% CI: 0.13–0.89) for AR2. The particularly favorable results observed in the T-ALLs and AR2 subgroups suggest the benefit of using DXM in specific patient groups and highlight the importance of risk stratification.

在此,我们报告了前瞻性队列研究 EORTC-CLG 58081 的结果,并将其与随机三期试验 EORTC-CLG 58951 的对照组进行了比较,在此基础上提出了治疗建议。在这两项研究中,年龄在1-18岁的BCR::ABL1阴性B系(B-ALL)或T系(T-ALL)急性淋巴细胞白血病患者均接受了BFM骨干治疗,但未进行头颅照射。与 58951 的对照组类似,泼尼松龙(PRED)60 毫克/平方米/天用于诱导治疗,但也做了一些修改。地塞米松(DXM)被用于平均风险2(AR2)T-ALL和B-ALL的诱导治疗,分别为10毫克/平方米/天和6毫克/平方米/天。开始使用大剂量甲氨蝶呤后,亮菌甲素抢救时间从36小时推迟到42小时,并增加了巩固后MRD时间点来对患者进行分层。2011年至2017年间,835名患者前瞻性地加入了58081研究。总体而言,58081与作为对照组的58951的5年无事件生存率(EFS)分别为84.8%对83.6%(危险比[HR],0.96[95%置信区间[CI]:0.76-1.21]),B-ALL为84.3%对84.9%(HR,1.06[99% CI:0.75-1.49]),但T-ALL为87.3%对76.6%(HR,0.59[99% CI:0.28-1.24])。两项研究在EFS方面的比较因风险组别而异(P = 0.012)。极低风险组的 HR 为 2.15(99% CI:0.67-6.85),而 AR2 组为 0.34(99% CI:0.13-0.89)。在T-ALLs和AR2亚组观察到的特别有利的结果表明,在特定患者群体中使用DXM是有益的,并强调了风险分层的重要性。
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引用次数: 0
Prognostic risk and survival of asymptomatic IgM monoclonal gammopathy: Results from a Spanish Multicenter Registry 无症状 IgM 单克隆丙种球蛋白病的预后风险和存活率:西班牙多中心登记的结果。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-12 DOI: 10.1002/hem3.70029
David F. Moreno, Cristina Jiménez, Fernando Escalante, Elham Askari, Marta Castellanos-Alonso, Mario Arnao, Ángela Heredia, Miguel Á. Canales, Magdalena Alcalá, Arancha Bermúdez, Ana Saus Carreres, María Casanova, Luis Palomera, Cristina Motlló, Ricarda García-Sánchez, Pablo Ríos Rull, Ramón García-Sanz, Carlos Fernández de Larrea

Asymptomatic IgM gammopathy encompasses IgM monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic Waldenström macroglobulinemia (AWM), both having a risk of progression to symptomatic disease. Here, we assessed the risk of progression and the mortality of 956 patients with asymptomatic IgM gammopathy across 25 Spanish centers. After a median follow-up of 5.7 years, 156 patients progressed, most of them to symptomatic WM (SWM). The cumulative incidence of progression was 13% and 20% at 5 and 10 years, respectively. The serum IgM ≥10 g/L, bone marrow (BM) infiltration ≥20%, β2-microglobulin ≥3 mg/L, and albumin <4 g/dL were the most potent predictors of disease progression in a multivariate Cox regression model, allowing the identification of three risk categories. The probability of progression to symptomatic disease at 5 years was 4.5%, 15.7%, and 42.8% for low-, intermediate-, and high-risk groups, respectively. In patients without a BM evaluation, the presence of none or 1 risk factor and 2 or 3 risk factors conferred a progression risk of 6% and 27% at 5 years, respectively. The model was independent of the presence of MYD88 L265P, which conferred a negative impact only in AWM patients. The relative survival (RS) ratio at 5 years of asymptomatic patients was similar to the Spanish population, which contrasted with the 0.76 5-year RS of SWM patients. Overall, the Spanish Multicenter Model comprehensively describes the risk of progression of asymptomatic patients and shows that the excess mortality is increased only in the symptomatic stage of the disease.

无症状 IgM 腺病包括意义未定的 IgM 单克隆腺病 (MGUS) 和无症状瓦尔登斯特伦巨球蛋白血症 (AWM),这两种疾病都有恶化为无症状疾病的风险。在此,我们对西班牙 25 个中心的 956 名无症状 IgM-丙种球蛋白病患者的病情恶化风险和死亡率进行了评估。在中位随访 5.7 年后,156 名患者病情恶化,其中大部分发展为有症状的 WM(SWM)。5年和10年的累积进展发生率分别为13%和20%。血清 IgM ≥10 g/L、骨髓(BM)浸润≥20%、β2-微球蛋白≥3 mg/L、白蛋白 MYD88 L265P 仅对 AWM 患者有负面影响。无症状患者的 5 年相对存活率(RS)与西班牙人群相似,而 SWM 患者的 5 年 RS 为 0.76。总体而言,西班牙多中心模型全面描述了无症状患者病情恶化的风险,并表明只有在疾病的无症状阶段,超额死亡率才会增加。
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引用次数: 0
Causes of death among patients diagnosed with chronic lymphocytic leukemia: A population-based study in the Netherlands, 1996–2020 慢性淋巴细胞白血病患者的死亡原因:1996-2020 年荷兰人口研究。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-12 DOI: 10.1002/hem3.70015
Lina van der Straten, Mark-David Levin, Manette A. W. Dinnessen, Otto Visser, Eduardus F. M. Posthuma, Jeanette K. Doorduijn, Anton W. Langerak, Arnon P. Kater, Avinash G. Dinmohamed

Chronic lymphocytic leukemia (CLL) manifests heterogeneously with varying outcomes. This population-based study examined causes of death (CODs), as registered by the physician who established the death, among 20,588 CLL patients diagnosed in the Netherlands between 1996 and 2020. Utilizing cause-specific flexible parametric survival models, we estimated cause-specific hazard ratios (HRs) and cumulative incidences of death due to CLL, solid malignancies, other hematological malignancies, infections, and other causes. Our findings reveal CLL as the predominant COD, contributing to around 40% of relative mortality, with a declining 5-year death probability from 16.8% in 1996–2002 to 7.6% in 2010–2020. Also, deaths attributed to solid malignancies, other hematological malignancies, and other COD diminished over time, as evidenced by respective HRs (95% confidence interval) of 0.68 (0.60%–0.77%), 0.45 (0.38%–0.53%), and 0.77 (0.66%–0.90%). In summary, our comprehensive, population-based analysis underscores a noticeable reduction in CLL-attributed deaths and other competing causes over the studied period. Nonetheless, CLL is registered as the most prevalent cause of mortality among contemporary diagnosed patients with CLL, emphasizing the continued relevance of CLL-centric clinical strategies and research.

慢性淋巴细胞白血病(CLL)表现各异,结果也各不相同。这项基于人群的研究调查了 1996 年至 2020 年间荷兰 20588 名确诊为慢性淋巴细胞白血病的患者的死亡原因(COD),死亡原因由确定死亡的医生登记。我们利用病因特异性灵活参数生存模型,估算了CLL、实体恶性肿瘤、其他血液恶性肿瘤、感染和其他病因导致的病因特异性危险比(HRs)和累计死亡发生率。我们的研究结果表明,CLL 是主要的慢性阻塞性肺病,约占相对死亡率的 40%,5 年死亡概率从 1996-2002 年的 16.8% 下降到 2010-2020 年的 7.6%。此外,随着时间的推移,实体恶性肿瘤、其他血液恶性肿瘤和其他慢性阻塞性肺疾病导致的死亡也在减少,其HRs(95%置信区间)分别为0.68(0.60%-0.77%)、0.45(0.38%-0.53%)和0.77(0.66%-0.90%)。总之,我们以人群为基础的综合分析表明,在研究期间,由 CLL 导致的死亡和其他竞争性原因导致的死亡明显减少。尽管如此,CLL 仍是当代确诊的 CLL 患者中最常见的死亡原因,这强调了以 CLL 为中心的临床策略和研究的持续相关性。
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引用次数: 0
Antibiotic-associated neutropenia is marked by the depletion of intestinal Lachnospiraceae and associated metabolites in pediatric patients 抗生素相关性中性粒细胞减少症的特点是,儿科患者肠道中的拉赫诺斯皮拉菌和相关代谢物消耗殆尽。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-07 DOI: 10.1002/hem3.70038
Josaura Fernandez-Sanchez, Rachel Rodgers, Arushana A. Maknojia, Nusrat Shaikh, Hannah Yan, Marlyd E. Mejia, Hope Hendricks, Robert R. Jenq, Pavan Reddy, Ritu Banerjee, Jeremy M. Schraw, Megan T. Baldridge, Katherine Y. King

Prolonged antibiotic exposure causes dangerous hematologic side effects, including neutropenia, in up to 34% of patients. Murine studies established a link between the intestinal microbiota and hematopoiesis. To identify factors that predispose to neutropenia in pediatric patients, we evaluated changes in microbiota-derived metabolites and intestinal microbiota composition after prolonged courses of antibiotics. In this multi-center study, patients with infections requiring anticipated antibiotic treatment of two or more weeks were enrolled. Stool samples were obtained at the start and completion of antibiotics or at neutropenia onset (prospective arm). Some patients were enrolled in a retrospective arm in which a stool sample was collected at the time of neutropenia during antibiotic therapy and 2–4 weeks after completion of antibiotics with recovery of blood counts. We identified 10 patients who developed neutropenia on antibiotics and 29 controls matched for age, sex, race, and ethnicity. Clinical data demonstrated no association between neutropenia and the type of infection or antibiotic used; however, patients with neutropenia were admitted to the intensive care unit more often and received longer courses of antibiotics. Reduced intestinal microbiome richness and, specifically, decreased abundance of Lachnospiraceae family members correlated with neutropenia. Untargeted stool metabolomic profiling revealed several metabolites that were depleted exclusively in patients with neutropenia, including members of the urea cycle pathway, pyrimidine metabolism, and fatty acid metabolism that are known to be produced by Lachnospiraceae. Our study shows a relationship between intestinal microbiota disruption and abnormal hematopoiesis and identifies taxa and metabolites likely to contribute to microbiota-sustained hematopoiesis.

长期接触抗生素会对血液系统产生危险的副作用,包括中性粒细胞减少症,这种副作用在患者中的比例高达 34%。小鼠研究证实了肠道微生物群与造血之间的联系。为了确定儿童患者中性粒细胞减少症的诱发因素,我们评估了长期服用抗生素后微生物群衍生代谢物和肠道微生物群组成的变化。在这项多中心研究中,我们招募了预计需要接受两周或两周以上抗生素治疗的感染患者。粪便样本在抗生素治疗开始和结束时或中性粒细胞减少症发病时采集(前瞻性研究组)。部分患者参加了回顾性研究,在抗生素治疗期间出现中性粒细胞减少时和抗生素治疗结束后 2-4 周血细胞计数恢复时采集粪便样本。我们确定了 10 名服用抗生素后出现中性粒细胞减少症的患者和 29 名年龄、性别、种族和民族相匹配的对照组患者。临床数据显示,中性粒细胞减少症与感染类型或使用的抗生素之间没有关联;但是,中性粒细胞减少症患者入住重症监护室的频率更高,接受抗生素治疗的疗程也更长。肠道微生物群丰富度降低,特别是拉赫诺斯皮拉科成员丰富度降低与中性粒细胞减少症有关。非靶向粪便代谢组学分析显示,中性粒细胞减少症患者体内有几种代谢物被完全消耗,其中包括已知由拉氏螺旋体产生的尿素循环途径、嘧啶代谢和脂肪酸代谢的成员。我们的研究显示了肠道微生物群破坏与异常造血之间的关系,并确定了可能有助于微生物群持续造血的类群和代谢物。
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