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30-Minute infusion of isatuximab in patients with newly diagnosed multiple myeloma: Results of a Phase 1b study analysis. 对新诊断的多发性骨髓瘤患者进行 30 分钟伊沙妥昔单抗输注:1b期研究分析结果。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-05 eCollection Date: 2024-11-01 DOI: 10.1002/hem3.70041
Enrique M Ocio, Aurore Perrot, Philippe Moreau, Maria-Victoria Mateos, Sara Bringhen, Joaquín Martínez-López, Lionel Karlin, Song-Yau Wang, Corina Oprea, Yi Li, Ercem Kodas, Jesus San-Miguel
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引用次数: 0
How to diagnose acid sphingomyelinase deficiency (ASMD) and Niemann-Pick disease type C from bone marrow and peripheral blood smears. 如何通过骨髓和外周血涂片诊断酸性鞘磷脂酶缺乏症(ASMD)和尼曼-皮克病 C 型。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-11-05 eCollection Date: 2024-11-01 DOI: 10.1002/hem3.70042
Sandrine Girard, Magali Pettazzoni, Roseline Froissart, Cécile Pagan, Thomas Boyer, Stephanie Dulucq, Valérie Gonçalves Monteiro, Nicolas Lechevalier, Marie Loosveld, Camille Lours, Caroline Mayeur-Rousse, Mélanie Pannetier, Caroline Peillon, Maria-Alessandra Rosenthal, Sonnthida Sep Hieng, Catherine Trichet, Lucile Baseggio
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引用次数: 0
GPRASP protein deficiency triggers lymphoproliferative disease by affecting B-cell differentiation GPRASP 蛋白缺乏会影响 B 细胞分化,从而引发淋巴组织增生性疾病。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-30 DOI: 10.1002/hem3.70037
Antonio Morales-Hernández, Emilia Kooienga, Heather Sheppard, Gabriela Gheorghe, Claire Caprio, Ashley Chabot, Shannon McKinney-Freeman

Gprasp1 and Gprasp2 encode proteins that control the stability and cellular trafficking of CXCR4, a master regulator of hematopoiesis whose dynamic regulation is required for appropriate trafficking of B-cells in the germinal center (GC). Here, we report that Gprasp1 and Gprasp2-deficient B-cells accumulate in the GC and show transcriptional abnormalities, affecting the mechanisms controlling Aicda expression and exposing them to excessive somatic hypermutation. Consequently, about 30% of mice transplanted with Gprasp-deficient hematopoietic stem and progenitor cells developed a biologically aggressive and fatal B-cell hyperproliferative disease by 20–50 weeks posttransplant. Histological and molecular profiling reveal that Gprasp1- and Gprasp2-deficient neoplasms morphologically resemble human high-grade B-cell lymphomas of germinal center origin with shared morphologic features of both Burkitt Lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), and molecular features consistent with DLBCL, as well as elevated mutational burden and heterogenous transcriptional and mutational signature. Thus, reduced Gprasp1 and Gprasp2 gene expression perturbs B-cell maturation and increases the risk of B-cell neoplasms of germinal center origin. As this model recapitulates the essential features of the heterogenous group of human hematopoietic malignancies, it could be a powerful tool to interrogate the mechanisms of lymphomagenesis for these cancers.

Gprasp1和Gprasp2编码控制CXCR4稳定性和细胞贩运的蛋白质,CXCR4是造血的主调节因子,B细胞在生殖中心(GC)的适当贩运需要它的动态调节。在这里,我们报告了 Gprasp1 和 Gprasp2 缺陷的 B 细胞在 GC 中聚集并显示出转录异常,影响了控制 Aicda 表达的机制,并使它们面临过度的体细胞超突变。因此,在移植了Gprasp缺陷造血干细胞和祖细胞的小鼠中,约有30%的小鼠在移植后20-50周出现了生物侵袭性和致命的B细胞过度增殖性疾病。组织学和分子谱分析显示,Gprasp1和Gprasp2缺陷型肿瘤在形态上类似于人类生殖中心起源的高级别B细胞淋巴瘤,具有伯基特淋巴瘤(BL)和弥漫大B细胞淋巴瘤(DLBCL)的共同形态特征,分子特征与DLBCL一致,以及突变负荷增加和异源转录与突变特征。因此,Gprasp1 和 Gprasp2 基因表达的减少会扰乱 B 细胞的成熟,并增加生殖中心来源 B 细胞肿瘤的风险。由于该模型再现了人类异质性造血恶性肿瘤的基本特征,因此它可以成为研究这些癌症淋巴致病机制的有力工具。
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引用次数: 0
Mitochondrial retention in mature red blood cells from patients with sickle cell disease is associated with stress erythropoiesis but not with proinflammatory state 镰状细胞病患者成熟红细胞中的线粒体滞留与红细胞生成压力有关,但与促炎状态无关
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-28 DOI: 10.1002/hem3.70030
Marc Romana, Sandrine Laurance, Marie-Dominique Hardy-Dessources, Laetitia Claer, Sylvie Ravion, Karim Dorgham, Yohann Garnier, Lea Kuznicki, Vanessa Tarer, Benoit Tressières, Sophie D. Lefevre, Veronique Baccini, Mariano A. Ostuni, Caroline Le Van Kim, Maryse Etienne-Julan
<p>Sickle cell disease (SCD) is a hemoglobinopathy characterized by the occurrence of vaso-occlusive events, severe chronic hemolytic anemia, and ultimately chronic complications and end-organ damages.<span><sup>1-3</sup></span> SCD pathophysiology has been shown to be extremely complex, resulting from microcirculatory dysfunctions associated with altered vaso-regulation and activation of inflammation cascades responsible of sterile inflammatory state, endothelial and neutrophil activation, and release of neutrophil extracellular trap (NET).<span><sup>1, 4-6</sup></span> More recently, a dysfunctional erythropoiesis has been described in SS patients characterized by high level of reticulocytes, increased apoptosis at the later stage of erythropoiesis, and abnormal retention of mitochondria in red blood cells (RBCs).<span><sup>7-13</sup></span> It is noteworthy that the functionality of these mitochondria in mature sickle RBCs remains controversial<span><sup>11, 12</sup></span> and mechanisms responsible for the mitochondrial retention during erythropoiesis have not been identified. Besides these unanswered points, several groups reported <i>in vitro</i> evidence that plasma mitochondrial DNA released by hemolysis of these abnormal RBCs could trigger type I interferon production<span><sup>12</sup></span> and NET release in SCD patients.<span><sup>13</sup></span> Altogether, these studies suggested that mitochondrial DNA from sickle mature RBCs could play a key role in the proinflammatory state associated with the disease.</p><p>In the present study, we characterized mature RBCs retaining mitochondria in a large cohort of the two main SCD genotypes, that is, SS and SC adult patients (71 and 40 patients, respectively) compared to 21 AA control individuals. We analyzed associations between mitochondria retention and hemolysis as well as inflammation markers (see patients and methods in Supporting Information and Supporting Information S1: Table 1 for the biological and demographic parameters).</p><p>Mitochondria presence in mature RBCs, total, and stress reticulocytes was assessed using flow cytometry (CD71/TO and/or MitoTracker Deep Red (MTKDR) staining) (Figure 1A). SS patients exhibited significant higher percentage of total circulating reticulocytes (5.0% ± 2.2%) compared to AA healthy donors (1.1% ± 0.4%), with a significant intermediate phenotype for SC patients (3.6% ± 1.7%) (Figure 1Bi). SS patients presented significant high levels of stress reticulocytes (2.6% ± 1.2%) compared to very low level observed in AA healthy donors (0.14 ± 0.09) while SC patients exhibited significant intermediate level (1.8% ± 1.0%) (Figure 1Bii). We did not observe significant difference of total and stress reticulocyte percentages between hydroxyurea (HU)-treated and nontreated SS patients (Figure 1Biii,iv). Percentage of mitochondria<sup>+</sup>-total reticulocytes was significantly higher in SS patients (25.0% ± 13.2%) compared to AA healthy donors (11.9% ± 8.
然而,cf 线粒体 DNA 的水平与红细胞中线粒体的保留无关,这表明检测到的 cf 线粒体 DNA 并不完全来自红细胞,而很可能来自中性粒细胞等其他循环细胞。这一假设得到了 Caielli 等人研究的支持,他们的研究表明中性粒细胞在体外释放 cf 线粒体 DNA 的能力与 NETs 的形成或坏死无关。我们认为线粒体的异常保留与患者的溶血状态有关,与炎症指标无关:概念化。Laetitia Claer、Karim Dorgham、Mariano A. Ostuni、Sandrine Laurance、Marc Romana、Maryse Etienne-Julan:概念化:方法论。Sandrine Laurance、Marc Romana、Mariano A. Ostuni、Caroline Le Van Kim、Maryse Etienne-Julan:方法:验证桑德琳-劳伦斯、马克-罗曼纳、马里亚诺-A-奥斯图尼、莱亚-库兹尼基、莱蒂西亚-克莱尔:形式分析:形式分析Lea Kuznicki、Laetitia Claer、Karim Dorgham、Marie-Dominique Hardy-Dessources、Sylvie Ravion、Yohann Garnier、Vanessa Tarer、Benoit Tressières、Sophie D. Lefevre:调查。Karim Dorgham、Maryse Etienne-Julan、Veronique Baccini:资源Sandrine Laurance、Marc Romana、Laetitia Claer、Lea Kuznicki、Mariano A. Ostuni、Caroline Le Van Kim、Maryse Etienne-Julan:数据整理桑德琳-劳伦斯、马克-罗曼纳:撰写原稿。Sandrine Laurance、Marc Romana、Mariano A. Ostuni、Caroline Le Van Kim、Maryse Etienne-Julan、Lea Kuznicki、Laetitia Claer:写作审阅和编辑。Sandrine Laurance、Marc Romana、Maryse Etienne-Julan:项目管理Sandrine Laurance、Marc Romana、Caroline Le Van Kim:项目管理:作者声明无利益冲突。这项工作得到了法国国家健康与医学研究院(Inserm)和GR-Ex卓越实验室的支持。
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引用次数: 0
Abstract Book 摘要手册
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-24 DOI: 10.1002/hem3.70012
<p>Alex F. Herrera<sup>1</sup>, Michael Leblanc<sup>2</sup>, Sharon M. Castellino<sup>3</sup>, Hongli Li<sup>2</sup>, Sarah Rutherford<sup>4</sup>, Andrew Evens<sup>5</sup>, Kelly Davison<sup>6</sup>, Angela Punnett<sup>7</sup>, Susan K. Parsons<sup>8</sup>, Sairah Ahmed<sup>9</sup>, Carla Casulo<sup>10</sup>, Nancy L. Bartlett<sup>11</sup>, Joseph Tuscano<sup>12</sup>, Matthew Mei<sup>1</sup>, Brian Hess<sup>13</sup>, Ryan Jacobs<sup>14</sup>, Hayder Saeed<sup>15</sup>, Pallawi Torka<sup>16</sup>, Boyu Hu<sup>17</sup>, Craig H. Moskowitz<sup>18</sup>, Supreet Kaur<sup>19</sup>, Gaurav Goyal<sup>20</sup>, Christopher Forlenza<sup>16</sup>, Andrew Doan<sup>21</sup>, Adam Lamble<sup>22</sup>, Pankaj Kumar<sup>23</sup>, Saeeda Chowdury<sup>24</sup>, Brett Brinker<sup>25</sup>, Namita Sharma<sup>26</sup>, Avina Singh<sup>27</sup>, Kristie Blum<sup>28</sup>, Anamarija Perry<sup>29</sup>, Alexandra Kovach<sup>21</sup>, David Hodgson<sup>30</sup>, Louis Constine<sup>10</sup>, Lale Kostakoglu<sup>31</sup>, Anca Prica<sup>30</sup>, Hildy Dillon<sup>32</sup>, Richard F. Little<sup>33</sup>, Margaret A. Shipp<sup>34</sup>, Michael Crump<sup>30</sup>, Brad S. Kahl<sup>11</sup>, John Leonard<sup>4</sup>, Sonali Smith<sup>35</sup>, Kara M. Kelly<sup>36</sup>, Jonathan W. Friedberg<sup>10</sup></p><p><sup>1</sup>City of Hope, <sup>2</sup>SWOG Statistics and Data Management Center, <sup>3</sup>Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, <sup>4</sup>Weill Cornell Medicine, <sup>5</sup>Rutgers Cancer Institute of New Jersey, <sup>6</sup>McGill University Health Center, <sup>7</sup>SickKids Hospital, <sup>8</sup>Tufts Medical Center, <sup>9</sup>MD Anderson Cancer Center, <sup>10</sup>University of Rochester, <sup>11</sup>Washington University in St. Louis, <sup>12</sup>UC Davis, <sup>13</sup>Medical University of South Carolina, <sup>14</sup>Levine Cancer Institute, <sup>15</sup>Moffitt Cancer Center, <sup>16</sup>Memorial Sloan Kettering Cancer Center, <sup>17</sup>Huntsman Cancer Institute, University of Utah, <sup>18</sup>University of Miami, <sup>19</sup>University of Texas at San Antonio, <sup>20</sup>University of Alabama at Birmingham, <sup>21</sup>Children's Hospital of Los Angeles, <sup>22</sup>Seattle Children's Hospital, <sup>23</sup>Illinois Cancer Care, <sup>24</sup>Prisma Health Cancer Institute, <sup>25</sup>Cancer & Hematology Center, <sup>26</sup>Geisinger Community Medical Center, <sup>27</sup>Fairview Ridges Hospital, <sup>28</sup>Emory University, Winship Cancer Institute, <sup>29</sup>University of Michigan, <sup>30</sup>Princess Margaret Cancer Centre, <sup>31</sup>University of Virginia, <sup>32</sup>SWOG Cancer Research Network, <sup>33</sup>National Cancer Institute, <sup>34</sup>Dana-Farber Cancer Institute, <sup>35</sup>University of Chicago, <sup>36</sup>Roswell Park Comprehensive Cancer Center</p><p><b>Figure 1:</b> Progression-Free Survival in in Modified Intent-to-treat Analysis Set.</p><p></p><p><b
Alex F. Herrera1、Michael Leblanc2、Sharon M. Castellino3、Hongli Li2、Sarah Rutherford4、Andrew Evens5、Kelly Davison6、Angela Punnett7、Susan K. Parsons8、Sairah Ahmed9、Carla Casulo10、Nancy L. Bartlett11、Joseph Tuscano12、Matthew Mei1、Brian Hess13、Ryan Jacobs14、Hayder Saeed15、Pallawi Torka16、Boyu Hu17、Craig H. Moskowitz18、Supreet Kaur19、Gaurav Goyal20、Christopher Forlenza16、Andrew Doan21、Adam Lamble22、Pankaj Kum23、Saeeda Chowdd.莫斯科维茨18、Supreet Kaur19、Gaurav Goyal20、Christopher Forlenza16、Andrew Doan21、Adam Lamble22、Pankaj Kumar23、Saeeda Chowdury24、Brett Brinker25、Namita Sharma26、Avina Singh27、Kristie Blum28、Anamarija Perry29、Alexandra Kovach21、David Hodgson30、Louis Constine10、Lale Kostakoglu31、Anca Prica30、Hildy Dillon32、Richard F.Little33、Margaret A. Shipp34、Michael Crump30、Brad S. Kahl11、John Leonard4、Sonali Smith35、Kara M. Kelly36、Jonathan W. Friedberg101City of Hope.Friedberg101City of Hope、2SWOG 统计与数据管理中心、3Aflac 癌症与血液疾病中心、亚特兰大儿童医疗中心、4Weill Cornell Medicine、5Rutgers Cancer Institute of New Jersey、6McGill University Health Center、7SickKids Hospital、8Tufts Medical Center、9MD Anderson Cancer Center、10University of Rochester、11Washington University in St.12戴维斯大学、13南卡罗来纳医科大学、14莱文癌症研究所、15莫菲特癌症中心、16纪念斯隆-凯特琳癌症中心、17犹他大学亨茨曼癌症研究所、18迈阿密大学、19德克萨斯大学圣安东尼奥分校、20阿拉巴马大学伯明翰分校、21洛杉矶儿童医院、22西雅图儿童医院、23伊利诺伊癌症护理中心、24普利斯玛健康癌症研究所、25癌症与坎普;血液学中心、26Geisinger Community Medical Center、27Fairview Ridges Hospital、28Emory University, Winship Cancer Institute、29University of Michigan、30Princess Margaret Cancer Centre、31University of Virginia、32SWOG Cancer Research Network、33National Cancer Institute、34Dana-Farber Cancer Institute、35University of Chicago、36Roswell Park Comprehensive Cancer Center 图 1:图 1:修正意向治疗分析集中的无进展生存期。背景:在晚期(AS)典型霍奇金淋巴瘤(cHL)的一线治疗中纳入布仑妥昔单抗韦多汀(BV)可改善儿童和成人患者(pts)的预后。我们假设,在AS cHL治疗中,引入PD-1阻断与尼妥珠单抗联合多柔比星、长春新碱和达卡巴嗪(N-AVD)将比BV-AVD改善无进展生存期(PFS),并在随机3期S1826研究中评估了这种方法。早期结果表明,N-AVD 在无进展生存期方面具有优势;在此,我们提供了中位随访 2 年(y)的最新数据:符合条件的患者年龄≥12岁,患有3-4期cHL。根据年龄、国际预后评分(IPS)和放疗意向(RT),患者按1:1随机分配到6个周期的N-AVD或BV-AVD。BV-AVD需要使用G-CSF,而N-AVD则不需要。在预先指定的患者中,允许对治疗结束 PET 上残留的代谢活跃病灶进行 RT。研究人员采用2014年卢加诺分类法评估反应和疾病进展。主要终点是PFS;次要终点包括安全性、无事件生存期(EFS)、患者报告结果和总生存期:994例患者于19年9月7日至5月22日期间入组,随机接受N-AVD(496例)或BV-AVD(498例)治疗。符合条件的患者有 970 人,组成了修改后的意向治疗队列。中位年龄为 27 岁(范围为 12-83 岁),56% 的患者为男性,76% 为白人,12% 为黑人,13% 为西班牙裔。24%的患者年龄为 18 岁,10%的患者年龄为 60 岁,32%的患者 IPS 为 4-7。各组中只有 7 例(0.7%)患者接受了 RT 治疗。中位随访时间为 2.1 年,N-AVD 的 PFS 优势持续存在(HR 0.45,95% CI 0.3-0.65,双侧 p &lt;0.001),N-AVD 治疗后 2 年的 PFS 为 92%,而 BV-AVD 治疗后为 83%。所有年龄、分期、IPS亚组的PFS获益情况一致。N-AVD 后的 EFS 也有所改善。BV-AVD 观察到 14 例死亡,而 N-AVD 观察到 7 例死亡。除中性粒细胞减少症和关节痛外,几乎所有不良事件在BV-AVD后都更常见,包括外周感觉神经病变(任何级别,29% N对56% BV)。两组患者的发热性中性粒细胞减少症和感染率相似,肺炎、结肠炎、胃炎和皮疹的发生率也相似:结论:与BV-AVD相比,N-AVD在青少年和成人AS cHL患者中的耐受性更好,PFS也有所改善。更长时间的随访证实了N-AVD在2年后的PFS获益,包括预先指定的亚组。N-AVD是治疗AS cHL的新标准。 Friedberg3、Andrea Gallamini4、Massimo Federico5、Eliza Hawkes6、David Hodgson7、Peter Johnson8、Eric Mou9、Kerry Savage10、Pier Luigi Zinzani11、Andrew Evens121美国明尼苏达州罗切斯特市梅奥诊所、2 美国马萨诸塞州波士顿塔夫茨医学中心,3 美国纽约罗切斯特大学医学中心,4 意大利尼斯安托万-拉卡萨涅癌症中心,5 意大
{"title":"Abstract Book","authors":"","doi":"10.1002/hem3.70012","DOIUrl":"https://doi.org/10.1002/hem3.70012","url":null,"abstract":"&lt;p&gt;Alex F. Herrera&lt;sup&gt;1&lt;/sup&gt;, Michael Leblanc&lt;sup&gt;2&lt;/sup&gt;, Sharon M. Castellino&lt;sup&gt;3&lt;/sup&gt;, Hongli Li&lt;sup&gt;2&lt;/sup&gt;, Sarah Rutherford&lt;sup&gt;4&lt;/sup&gt;, Andrew Evens&lt;sup&gt;5&lt;/sup&gt;, Kelly Davison&lt;sup&gt;6&lt;/sup&gt;, Angela Punnett&lt;sup&gt;7&lt;/sup&gt;, Susan K. Parsons&lt;sup&gt;8&lt;/sup&gt;, Sairah Ahmed&lt;sup&gt;9&lt;/sup&gt;, Carla Casulo&lt;sup&gt;10&lt;/sup&gt;, Nancy L. Bartlett&lt;sup&gt;11&lt;/sup&gt;, Joseph Tuscano&lt;sup&gt;12&lt;/sup&gt;, Matthew Mei&lt;sup&gt;1&lt;/sup&gt;, Brian Hess&lt;sup&gt;13&lt;/sup&gt;, Ryan Jacobs&lt;sup&gt;14&lt;/sup&gt;, Hayder Saeed&lt;sup&gt;15&lt;/sup&gt;, Pallawi Torka&lt;sup&gt;16&lt;/sup&gt;, Boyu Hu&lt;sup&gt;17&lt;/sup&gt;, Craig H. Moskowitz&lt;sup&gt;18&lt;/sup&gt;, Supreet Kaur&lt;sup&gt;19&lt;/sup&gt;, Gaurav Goyal&lt;sup&gt;20&lt;/sup&gt;, Christopher Forlenza&lt;sup&gt;16&lt;/sup&gt;, Andrew Doan&lt;sup&gt;21&lt;/sup&gt;, Adam Lamble&lt;sup&gt;22&lt;/sup&gt;, Pankaj Kumar&lt;sup&gt;23&lt;/sup&gt;, Saeeda Chowdury&lt;sup&gt;24&lt;/sup&gt;, Brett Brinker&lt;sup&gt;25&lt;/sup&gt;, Namita Sharma&lt;sup&gt;26&lt;/sup&gt;, Avina Singh&lt;sup&gt;27&lt;/sup&gt;, Kristie Blum&lt;sup&gt;28&lt;/sup&gt;, Anamarija Perry&lt;sup&gt;29&lt;/sup&gt;, Alexandra Kovach&lt;sup&gt;21&lt;/sup&gt;, David Hodgson&lt;sup&gt;30&lt;/sup&gt;, Louis Constine&lt;sup&gt;10&lt;/sup&gt;, Lale Kostakoglu&lt;sup&gt;31&lt;/sup&gt;, Anca Prica&lt;sup&gt;30&lt;/sup&gt;, Hildy Dillon&lt;sup&gt;32&lt;/sup&gt;, Richard F. Little&lt;sup&gt;33&lt;/sup&gt;, Margaret A. Shipp&lt;sup&gt;34&lt;/sup&gt;, Michael Crump&lt;sup&gt;30&lt;/sup&gt;, Brad S. Kahl&lt;sup&gt;11&lt;/sup&gt;, John Leonard&lt;sup&gt;4&lt;/sup&gt;, Sonali Smith&lt;sup&gt;35&lt;/sup&gt;, Kara M. Kelly&lt;sup&gt;36&lt;/sup&gt;, Jonathan W. Friedberg&lt;sup&gt;10&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;&lt;sup&gt;1&lt;/sup&gt;City of Hope, &lt;sup&gt;2&lt;/sup&gt;SWOG Statistics and Data Management Center, &lt;sup&gt;3&lt;/sup&gt;Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, &lt;sup&gt;4&lt;/sup&gt;Weill Cornell Medicine, &lt;sup&gt;5&lt;/sup&gt;Rutgers Cancer Institute of New Jersey, &lt;sup&gt;6&lt;/sup&gt;McGill University Health Center, &lt;sup&gt;7&lt;/sup&gt;SickKids Hospital, &lt;sup&gt;8&lt;/sup&gt;Tufts Medical Center, &lt;sup&gt;9&lt;/sup&gt;MD Anderson Cancer Center, &lt;sup&gt;10&lt;/sup&gt;University of Rochester, &lt;sup&gt;11&lt;/sup&gt;Washington University in St. Louis, &lt;sup&gt;12&lt;/sup&gt;UC Davis, &lt;sup&gt;13&lt;/sup&gt;Medical University of South Carolina, &lt;sup&gt;14&lt;/sup&gt;Levine Cancer Institute, &lt;sup&gt;15&lt;/sup&gt;Moffitt Cancer Center, &lt;sup&gt;16&lt;/sup&gt;Memorial Sloan Kettering Cancer Center, &lt;sup&gt;17&lt;/sup&gt;Huntsman Cancer Institute, University of Utah, &lt;sup&gt;18&lt;/sup&gt;University of Miami, &lt;sup&gt;19&lt;/sup&gt;University of Texas at San Antonio, &lt;sup&gt;20&lt;/sup&gt;University of Alabama at Birmingham, &lt;sup&gt;21&lt;/sup&gt;Children's Hospital of Los Angeles, &lt;sup&gt;22&lt;/sup&gt;Seattle Children's Hospital, &lt;sup&gt;23&lt;/sup&gt;Illinois Cancer Care, &lt;sup&gt;24&lt;/sup&gt;Prisma Health Cancer Institute, &lt;sup&gt;25&lt;/sup&gt;Cancer &amp; Hematology Center, &lt;sup&gt;26&lt;/sup&gt;Geisinger Community Medical Center, &lt;sup&gt;27&lt;/sup&gt;Fairview Ridges Hospital, &lt;sup&gt;28&lt;/sup&gt;Emory University, Winship Cancer Institute, &lt;sup&gt;29&lt;/sup&gt;University of Michigan, &lt;sup&gt;30&lt;/sup&gt;Princess Margaret Cancer Centre, &lt;sup&gt;31&lt;/sup&gt;University of Virginia, &lt;sup&gt;32&lt;/sup&gt;SWOG Cancer Research Network, &lt;sup&gt;33&lt;/sup&gt;National Cancer Institute, &lt;sup&gt;34&lt;/sup&gt;Dana-Farber Cancer Institute, &lt;sup&gt;35&lt;/sup&gt;University of Chicago, &lt;sup&gt;36&lt;/sup&gt;Roswell Park Comprehensive Cancer Center&lt;/p&gt;&lt;p&gt;&lt;b&gt;Figure 1:&lt;/b&gt; Progression-Free Survival in in Modified Intent-to-treat Analysis Set.&lt;/p&gt;&lt;p&gt;&lt;/p&gt;&lt;p&gt;&lt;b","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142524543","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
Long-term outcome of 2-year survivors after allogeneic hematopoietic cell transplantation for acute leukemia 急性白血病异基因造血细胞移植后两年幸存者的长期预后。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-22 DOI: 10.1002/hem3.70026
Marion Larue, Myriam Labopin, Thomas Schroeder, Xiao-jun Huang, Igor W. Blau, Johannes Schetelig, Arnold Ganser, Rose-Marie Hamladji, Wolfgang Bethge, Nicolaus Kröger, Gerard Socié, Urpu Salmenniemi, Henrik Sengeloev, Bhagirathbhai Dholaria, Bipin N. Savani, Arnon Nagler, Fabio Ciceri, Mohamad Mohty

Information on late complications in patients with acute leukemia who have undergone allogeneic hematopoietic cell transplantation (HCT) is limited. We performed a left-truncated analysis of long-term survival in patients with acute leukemia who were alive and disease-free 2 years after HCT. We included 2701 patients with acute lymphoblastic leukemia (ALL) and 9027 patients with acute myeloid leukemia (AML) who underwent HCT between 2005 and 2012. The 10-year overall survival (OS) rate was 81.3% for ALL and 76.2% for AML, with the main causes of late mortality being relapse (ALL-33.9%, AML-44.9%) and chronic graft-versus-host disease (ALL-29%, AML-18%). At 10 years, HCT-related mortality was 16.8% and 20.4%, respectively. Older age and unrelated donor transplantation were associated with a worse prognosis for both types of leukemia. In addition, transplantation in the second or third complete remission and peripheral blood HSC for ALL are associated with worse outcomes. Similarly, adverse cytogenetics, female donor to male patient combination, and reduced intensity conditioning in AML contribute to poor prognosis. We conclude that 2-year survival in remission after HCT for acute leukemia is encouraging, with OS of nearly 80% at 10 years. However, the long-term mortality risk of HCT survivors remains significantly higher than that of the age-matched general population. These findings underscore the importance of tailoring transplantation strategies to improve long-term outcomes in patients with acute leukemia undergoing HCT.

有关接受异基因造血细胞移植(HCT)的急性白血病患者晚期并发症的信息非常有限。我们对 HCT 术后 2 年存活且无病的急性白血病患者的长期生存情况进行了左截断分析。我们纳入了 2005 年至 2012 年期间接受 HCT 的 2701 名急性淋巴细胞白血病(ALL)患者和 9027 名急性髓性白血病(AML)患者。ALL患者的10年总生存率(OS)为81.3%,AML患者为76.2%,晚期死亡的主要原因是复发(ALL-33.9%,AML-44.9%)和慢性移植物抗宿主疾病(ALL-29%,AML-18%)。10年后,HCT相关死亡率分别为16.8%和20.4%。高龄和非亲缘供体移植与两种类型白血病的较差预后有关。此外,在第二次或第三次完全缓解时进行移植以及外周血造血干细胞用于 ALL 与较差的预后有关。同样,不良细胞遗传学、女性供者与男性患者的组合以及急性髓细胞白血病的减量调理也会导致预后不良。我们的结论是,急性白血病造血干细胞移植后的2年缓解期生存率令人鼓舞,10年的OS接近80%。然而,HCT 幸存者的长期死亡风险仍明显高于年龄匹配的普通人群。这些发现强调了调整移植策略以改善接受 HCT 的急性白血病患者长期预后的重要性。
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引用次数: 0
Casting light on the national mission to eliminate sickle cell disease in India 揭示印度消除镰状细胞病的国家使命
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-19 DOI: 10.1002/hem3.70033
Frédéric B. Piel, Roshan Colah, Dipty L. Jain
<p>Sickle cell disease (SCD) is a neglected global public health burden.<span><sup>1</sup></span> Although it primarily affects populations from sub-Saharan Africa,<span><sup>2</sup></span> SCD is also prevalent across the Indian subcontinent, particularly among tribal (or scheduled) populations.<span><sup>3</sup></span> India is the most populated country in the world. According to the latest population estimates of the United Nations World Population Prospects,<span><sup>4</sup></span> its population includes 1.441 billion people, and it is expected to further increase to reach 1.697 billion in 2063. India ranks as the country with the third highest number of annual births affected by SCD, after Nigeria and the Democratic Republic of the Congo.<span><sup>2</sup></span> Although SCD has long been considered to be mild across the Indian subcontinent, recent evidence has demonstrated that there was a much wider range of severity than previously thought.<span><sup>5</sup></span> Finally, tribal populations tend to be largely over-represented in the low socio-economic groups across India, making them a vulnerable group for many communicable and non-communicable diseases.<span><sup>6</sup></span></p><p>Interventions to reduce SCD morbidity and mortality, such as newborn screening, vaccinations, penicillin prophylaxis, and hydroxyurea, have proven to be effective in large-scale studies in high- and upper-middle-income countries, including the United States,<span><sup>7</sup></span> United Kingdom,<span><sup>8</sup></span> Jamaica,<span><sup>9</sup></span> and Brazil.<span><sup>10</sup></span> Pilot studies of these interventions have been conducted in numerous low-income countries.<span><sup>11</sup></span> Cost-benefit analyses conducted in sub-Saharan Africa<span><sup>12</sup></span> and India<span><sup>13</sup></span> suggested that these interventions would also be effective in these settings. Nevertheless, due to a lack of political and financial commitments, no national program has so far been launched in a low- or lower-middle-income country of high prevalence for SCD. Despite the curative promises of gene therapies,<span><sup>14</sup></span> there is an urgent need to scale up interventions in the most affected countries to improve the quality of life of patients affected and reduce the global burden of SCD.<span><sup>11</sup></span></p><p>In July 2023, the Government of India launched the “National Sickle Cell Anaemia Elimination Mission.”<span><sup>15</sup></span> Although this program was officially launched by Prime Minister Modi, it did not receive much attention internationally. The stated aims of the Mission are twofold: (i) to improve the care of all SCD patients for their better future and (ii) to lower the prevalence of the disease by 2047 through a multifaceted coordinated approach toward screening and awareness strategies. The ambitious plan at launch was to screen 70 million people across India over the first 3 years of the Missio
镰状细胞病(SCD)是一种被忽视的全球公共卫生负担。1 虽然镰状细胞病主要影响撒哈拉以南非洲地区的人口,2 但它在印度次大陆也很普遍,尤其是在部落(或在册人口)中。3 印度是世界上人口最多的国家。根据联合国《世界人口展望》4 的最新人口估计,印度人口为 14.41 亿,预计到 2063 年将进一步增至 16.97 亿。2 虽然长期以来人们一直认为印度次大陆的 SCD 病情较轻,但最近的证据表明,其严重程度的范围比以前想象的要大得多。5 最后,印度各地的部落人口往往在社会经济地位较低的群体中占很大比例,这使他们成为许多传染性和非传染性疾病的易感人群。在美国、7 英国、8 牙买加9 和巴西10 等高收入和中上收入国家进行的大规模研究证明,新生儿筛查、疫苗接种、青霉素预防和羟基脲等降低 SCD 发病率和死亡率的干预措施是有效的。然而,由于缺乏政治和财政承诺,迄今为止还没有一个国家在 SCD 高发的低收入或中低收入国家启动国家计划。11 2023 年 7 月,印度政府启动了 "消除镰状细胞性贫血国家使命"(National Sickle Cell Anaemia Elimination Mission)15 。尽管该计划由莫迪总理正式启动,但在国际上并未引起广泛关注。该计划的既定目标有两个:(i) 改善对所有镰状细胞性贫血患者的护理,让他们拥有更美好的未来;(ii) 到 2047 年,通过多方面协调的筛查和宣传策略,降低该疾病的患病率。启动之初的雄心勃勃的计划是在该计划的头 3 年对全印度 7000 万人进行筛查。该计划推荐的筛查方法是溶解度镰状试验(阳性病例需经黄金标准高效液相色谱法(HPLC)确认)或近十年来出现的快速护理点检测(POCT)设备。溶解度检测无法区分镰状细胞性病(SCD)的同基因型患者(SS)和镰状细胞性状(SCT)的异基因型患者(AS)。此外,在用于新生儿筛查时,由于存在大量胎儿血红蛋白(HbF),当 HbS 占总血红蛋白的比例低于 10%时,假阴性率很高。因此,在高收入国家,溶解度检测往往只用于紧急筛查。高效液相色谱法(HPLC)验证往往成本高昂,依赖于技术精湛的工作人员、需要定期维护的精密设备和可用试剂。因此,可能没有系统地进行确证试验来验证溶解度镰状试验的结果。POCT 设备有可能提供一种有前途的替代方法,尤其是在大城市以外的地区。16 目前的 POCT 通常可以区分 SCD 和 SCT,但不能鉴别镰状细胞-β地中海贫血。最近开发的 GazelleTM 设备旨在解决这一局限性。17 一些 POCT 设备(如 SickleScanTM 或 HemoTypeSCTM)的灵敏度和特异性已在严格的国内18、19 和国际研究中得到验证。虽然印度医学研究理事会 (ICMR) 已对几种筛查方法进行了正式验证,但样本量相对较小,而且有几种检测方法声称其敏感性和特异性均为 100%。目前迫切需要采用国际公认的标准协议对这些方法进行独立验证,特别是对 POCT 设备进行独立验证。 鉴于已确认的 SCD 患者需要接受治疗,在当地生产羟基脲(目前用于预防 SCD 并发症的主要药物)也产生了类似的影响。截至 2024 年 9 月 17 日,印度全国共筛查了 42,139,843 人,其中 163,765 人被确定为 SCD(0.39%),1,144,274 人被确定为 SCT(2.72%)(表 1)。另有 398,628 人(0.95%)的筛查结果显示仍在确认过程中。该仪表板没有提供地区或种族细分,但这些初步数据为了解该计划在印度的规模提供了宝贵的信息。22 该计划启动仅 1 年多,筛查人数已超过 4200 万。相比之下,这一数字是美国新生儿普遍筛查计划每年检测人数(约 360 万)的 10 倍以上,是英国新生儿普遍筛查计划每年检测人数(约 60 万)的 70 倍。这项计划的规模意味着,平均每天都有将近 400 例新的 SCD 病例可能被特派团发现。这大致相当于英国一年中新发现的受影响新生儿数量。此外,每天还能发现约 2500 名携带者。虽然从临床角度来看,这些人并不值得关注,但他们与 SCD 的未来负担密切相关,因此应向他们介绍该疾病,并为他们提供婚前筛查23 和遗传咨询24。对撒哈拉以南非洲成人的调查发现,由于与 SCD 相关的婴儿死亡率较高,SCD 患者的人数往往比预期的要少得多。26 虽然在印度观察到的与预期的人数之间的差异可能是由一系列复杂的因素造成的,但在印度,尤其是在部落人群中,近亲结婚的程度很高。28 尽管调查团的初步数据表明,单单预防近亲结婚就有可能使印度每年的 SCD 新生儿人数大幅减少。这也将影响包括先天性畸形在内的其他各种健康后果的发生率。29 此外,在这样一个幅员辽阔、文化多样的国家,了解文化习俗和传统至关重要,尤其是在考虑到部落人口时,他们往往被边缘化,在社会经济地位较低的群体中所占比例过高。来自英国巴基斯坦社区的证据表明,即使是在原籍国以外的多民族社区,变化也往往是几代人慢慢发生的。30 同样,沙特阿拉伯实施的强制计划也凸显了在一个人口少得多且财力雄厚的国家采取此类干预措施的复杂性。31 筛查是识别 SCD 患者并管理他们及其并发症的必要第一步。31 筛查是识别 SCD 患者并处理他们及其并发症的必要的第一步。然而,教育材料、医疗保健设施、专科人员和治疗方案的可获得性和可及性对于成功随访已识别的 SCD 患者以及理想情况下的携带者也是至关重要的。作为 "使命 "的一部分,已经用印地语和英语编写了几份指南和培训材料32 ,但目前有关其使用情况的信息很少。目前还没有关于该计划影响的公开数据,但跟踪随访率、羟基脲的使用情况、并发症发生率的变化以及对该疾病的认识是否因这一全国性举措而有所改变,将是该计划能否取得成功的关键。可靠的数据对于证明该计划的益处和确保其可持续性至关重要。在该计划实施的头 3 年,印度只有 5%的人口接受了筛查。印度全国每年约有 2500 万新生儿,因此需要在全国范围内持续努力,才能实现与美国或英国目前实施的新生儿筛查计划相当的普及计划。 如果这是长期目标,就需要持续的政治意愿和财政资源。在这样一个大规模倡议中使用的词汇非常重要,需要仔细斟酌。这项任务中使用的 "消除 "一词让人联想到用于包括疟疾在内的传染病的雄心勃勃的战略。33 考虑到 SCD 的遗传性质,这一术语是令人遗憾的。应将该计划作为一个契机,以减少影响印度人口的不平等现象,并减轻整个次大陆未来的 SCD 负担,而不是进一步污名化部落人口或可能助长优生学宣传。在印度这样一个幅员辽阔、人口众多的国家,能够如此迅速地实施如此大规模的计划,实在令人惊叹。在短短一年多的时间里,就有 4000 多万人接受了筛查,治疗一种在很大程度上被忽视的疾病,这是一项了不起的成就,值得庆祝。然而,还需要制定严格的程序,以确保筛查设备和方案符合国际标准,并在全国范围内始终如一地遵循指导方针,从而产生高质量的流行病学数据。特派团在国内和国际上的公信力有赖于可靠的数据。还需要进行成本效益分析,以证明这一举措的影响。最后,这项任务的成功对于证明在撒哈拉以南非洲国家实施大规模 SCD 计划的可行性具有重要意义。Frédéri
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引用次数: 0
Promoting and supporting leadership in hematology departments 促进和支持血液科的领导能力
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-17 DOI: 10.1002/hem3.70028
Roch Houot, Emmanuel Gyan
<p>In recent years, the hospital system has faced tremendous pressure from economic and societal crises, which were further aggravated by the COVID-19 pandemic. Today, the European healthcare system is in a continuous crisis, primarily due to underinvestment and workforce shortages.<span><sup>1</sup></span> In such a situation, management skills at all levels of hospital departments become critical, especially for heads of departments—a position historically driven in many countries, including France, by academic rather than managerial competencies.</p><p>Challenges with medical staff retention have also exacerbated the workload of healthcare professionals.<span><sup>2</sup></span> The shortage of healthcare workers in Europe is projected to reach 4.1 million by 2030, including 0.6 million physicians.<span><sup>3</sup></span> Workforce shortages contribute to burnout among physicians and other healthcare workers, which renders the tasks of heads of departments extremely challenging.<span><sup>4, 5</sup></span></p><p>In the past two decades, the practice of hematology has experienced accelerated advancements in diagnostics and therapeutics, with notable prolongation of patient survival, albeit at the cost of intensified medical care due to the novel time-consuming therapeutic approaches. As such, the diversity of hematologic diagnoses and specialized treatments have created an expanding curriculum with ever more limited human resources.<span><sup>2, 6</sup></span> The number of hematologic specialists and the competence of their training have become a concern in European countries.<span><sup>6</sup></span></p><p>The European Hematology Association (EHA) has created solutions for training in hematology, including the European Hematology curriculum, developed through a “bottom-up” process, which has inspired national educational initiatives.<span><sup>6</sup></span> The European Working Time Directive (EWTD), introduced in 2004, aims to reduce long working hours to enhance patient safety. In this context, the European Commission urged member states to adopt the EWTD for hospital physicians.<span><sup>2</sup></span> However, these initiatives create challenges for department heads, who must manage increased workloads with limited staffing and heightened awareness of the adverse effects of inadequate organization on workers' health.</p><p>In a recent survey conducted with 2390 university hospital faculty members in France between October and December 2021, 40% of participants had severe burnout, 14% had suicidal ideation, and 12% had job strain.<span><sup>4</sup></span> The factors associated with the unfavorable experiences included heavy work overload, work-life imbalance, and perceived lack of support from the institution.<span><sup>4, 7</sup></span> Although the impact of stressful events on the risk of burnout and suicide is undeniable, many personality traits, such as emotional stability, extraversion, and social integration, play a role.<span><
法国血液科主任团体的目标是提高管理技能,从根本上重建医疗系统。这一举措符合法国政府的决定,即在医疗部门建立更多的自主权,使科室主任成为医院管理的核心。11 这反过来又意味着,受过管理培训的科室主任除了承担临床和学术职责外,还要准备好参与医院所需的多方利益相关者组织。科室主任对科室的内部结构和医疗团队的工作生活质量做出了巨大贡献,并在组织、相关性、医疗质量和安全、医疗和辅助医疗团队的本地管理以及研究员和医学生的管理等方面构成了参考水平。2 例如,靶向疗法和免疫疗法的成功彻底改变了各种血液病的治疗格局,改善了患者的预后,包括延长了生存期。因此,血液病学家面临着新的挑战,需要持续研究、多学科合作和专业知识,以优化患者预后,确保在临床实践中安全有效地使用这些疗法。考虑到新型疗法的复杂性和癌症幸存者人数的增加,医生的职业负担也在加重。13 随着优秀的医生离开公立医院,加入经济待遇更好、条件更优越的其他医院,血液科也面临着人员短缺的问题。2 有必要采取措施,增加对医疗系统或医院预算的投资,以留住并吸引医疗专业人员,从而抵消临床负担过重的影响。另一项举措包括将耗时的任务委托给非医务人员,包括实验室的生物医 学科学家和临床护理专家,如英国国民健康服务所做的那样。专业协会和社区的干预措施在预防和管理个人负担加重方面发挥着重要作用。已发表的研究强调了职业倦怠在欧洲肿瘤学家中的普遍性,并在国家和国际大会上加强了宣传活动,13 欧洲血液学协会正在解决年轻血液学家中的这一问题。15 必须收集欧洲各年龄段血液学家中职业倦怠普遍性的数据,以呼吁投资采取措施,使血液学成为对年轻和资深医生都有吸引力的领域。然而,这与现实相去甚远。为此,有必要自下而上地重建医院系统,以适应行政管理的变化。参与支持性网络,如我们正在建立的社区,可以分享经验和学习机会。这个由血液科负责人组成的社区是提供管理支持的有力工具。鉴于这种社区的个人和组织主动性,我们鼓励其他专业科室的负责人积极参与社区建设,自下而上地为医院组织、结构和功能的重建做出贡献。同样,与欧洲其他国家的科室负责人进行这种交流,也必将有助于分享不同的护理和组织模式,从而相互启发。
{"title":"Promoting and supporting leadership in hematology departments","authors":"Roch Houot,&nbsp;Emmanuel Gyan","doi":"10.1002/hem3.70028","DOIUrl":"https://doi.org/10.1002/hem3.70028","url":null,"abstract":"&lt;p&gt;In recent years, the hospital system has faced tremendous pressure from economic and societal crises, which were further aggravated by the COVID-19 pandemic. Today, the European healthcare system is in a continuous crisis, primarily due to underinvestment and workforce shortages.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; In such a situation, management skills at all levels of hospital departments become critical, especially for heads of departments—a position historically driven in many countries, including France, by academic rather than managerial competencies.&lt;/p&gt;&lt;p&gt;Challenges with medical staff retention have also exacerbated the workload of healthcare professionals.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The shortage of healthcare workers in Europe is projected to reach 4.1 million by 2030, including 0.6 million physicians.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Workforce shortages contribute to burnout among physicians and other healthcare workers, which renders the tasks of heads of departments extremely challenging.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In the past two decades, the practice of hematology has experienced accelerated advancements in diagnostics and therapeutics, with notable prolongation of patient survival, albeit at the cost of intensified medical care due to the novel time-consuming therapeutic approaches. As such, the diversity of hematologic diagnoses and specialized treatments have created an expanding curriculum with ever more limited human resources.&lt;span&gt;&lt;sup&gt;2, 6&lt;/sup&gt;&lt;/span&gt; The number of hematologic specialists and the competence of their training have become a concern in European countries.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The European Hematology Association (EHA) has created solutions for training in hematology, including the European Hematology curriculum, developed through a “bottom-up” process, which has inspired national educational initiatives.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; The European Working Time Directive (EWTD), introduced in 2004, aims to reduce long working hours to enhance patient safety. In this context, the European Commission urged member states to adopt the EWTD for hospital physicians.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; However, these initiatives create challenges for department heads, who must manage increased workloads with limited staffing and heightened awareness of the adverse effects of inadequate organization on workers' health.&lt;/p&gt;&lt;p&gt;In a recent survey conducted with 2390 university hospital faculty members in France between October and December 2021, 40% of participants had severe burnout, 14% had suicidal ideation, and 12% had job strain.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; The factors associated with the unfavorable experiences included heavy work overload, work-life imbalance, and perceived lack of support from the institution.&lt;span&gt;&lt;sup&gt;4, 7&lt;/sup&gt;&lt;/span&gt; Although the impact of stressful events on the risk of burnout and suicide is undeniable, many personality traits, such as emotional stability, extraversion, and social integration, play a role.&lt;span&gt;&lt;","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449032","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
Overcoming a T-ALL order: A comprehensive study linking genomics to clinical outcomes 战胜 T-ALL 订单:将基因组学与临床结果联系起来的综合研究
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-13 DOI: 10.1002/hem3.70027
Yizhou Huang, Charles E. de Bock
<p>Acute lymphoblastic leukemia (ALL) remains a leading success story of how modern therapies have improved patient outcomes from less than 10% survival rate in the 1950s to exceeding 90% today. This has been in part from the decades of research in the optimal use of chemotherapeutics, and, for B-cell ALL (B-ALL), the implementation of risk stratification based on clinical factors (e.g., age and peripheral blood cell counts), minimal/measurable residual disease (MRD), and cytogenetics (favorable, neutral, or unfavorable). However, for T-cell ALL (T-ALL), risk stratification is currently only based on MRD levels at the end of induction and again at the end of consolidation therapy with genomics and cytogenetics not considered prognostic factors in treatment decision-making.<span><sup>1</sup></span> In an effort to include genomics into the risk stratification for T-ALL, a new study led by Charles Mullighan and David Teachey<span><sup>2</sup></span> has now been published as a landmark analysis of 1300 uniformly treated T-ALL cases that, for the first time, not only defines a total of 15 discrete genetic subtypes but also links them to clinical outcomes.</p><p>This new study integrates whole genome sequencing (WGS), whole exome sequencing (WES), and whole transcriptome sequencing data to expand the classification of T-ALL into a total of 15 different subtypes (Figure 1). The most significant variation from the current classification is the definition of two new subtypes, including a new early T-cell precursor (ETP)-like ALL subtype and an LMO2 γδ-like subtype—both of which have a diverse set of genetic alterations. Of the many genetic alterations, an interesting discriminator is the <i>KMT2A</i> fusions present in the ETP-like subtype being mostly <i>KMT2A::AFDN</i> fusion, while the non-ETP subtypes exclusively have <i>KMT2A::MLLT1</i> fusion. The authors also compared the gene expression signatures of all 15 subtypes with normal hematopoietic and T-cell development cell stages. They found that the different T-ALL subtypes mapped across the entire continuum of T-cell development, supporting the hypothesis that each subtype represented a “frozen” stage of cellular differentiation. In the case of the ETP-like subtype, despite the heterogenous genetic drivers, the most likely cell of origin was found to be hematopoietic stem and progenitor cells (HSPC).</p><p>It will come as no surprise that this study confirms the high frequency of recurrent <i>NOTCH1</i> mutations (69% of cases) in T-ALL, second only to <i>CDKN2A</i> alterations (71% of cases), with the majority being coding sequence mutations that lead to activation of NOTCH1 signaling. However, this study also found rare single-nucleotide variants (SNV) within intron 28 of the <i>NOTCH1</i> gene which generated a new splice acceptor site and resulted in a 43 amino acid insertion between the heterodimerization (HD) domain and the transmembrane (TM) domain of NOTCH1. Functionally, this new mutation
一个有趣的发现是,对于 KMT2A 基因重排的患者,亚型背景对临床结果和风险分组至关重要。例如,ETP 样和 KMT2A 亚型 T-ALL 患者被列为 "极高风险",而非 ETP 样和 KMT2A 亚型患者则被列为 "低风险"。SPI1 亚型也很有趣,因为虽然被归类为 "极高风险",但他们更有可能是 MRD 阴性。他们的不良预后部分是由于发生了同样携带 SPI1 融合体的继发性恶性肿瘤。最近发现,携带 SPI1 融合的 T-ALL 病例对达沙替尼高度敏感。因此,这项新研究显示,携带 SPI1 融合基因的患者极易发展为继发性恶性肿瘤,因此在治疗中可以考虑尽早使用达沙替尼,尽管激酶抑制剂的使用是否会改变 T-ALL 克隆和继发性恶性肿瘤的发展轨迹还有待观察。那么,这项新研究如何改变新诊断的 T-ALL 患者的管理,这种新的风险分层是否可以前瞻性地使用?令人欣慰的是,作者在开发这些风险模型时考虑到了临床转化,因此可以通过重点选择的特征对新的 T-ALL 患者进行分层。因此,如果前瞻性地应用这些模型,被归类为 "极高风险 "的患者可以快速进行骨髓移植。相反,对于 "低风险 "患者(如 MRD 阴性、非 ETP-like KMT2A 亚型),可以降低强化化疗的强度,或引入无治疗间隔期。这些方法可能有助于控制化疗的毒副作用,潜在地改善患者的生活质量,而不会对临床结果产生不利影响(图1)。这项研究为研究T-ALL生物学的研究人员提供了大量新信息,也为临床医生提供了大量新信息,有助于在获得下一代测序数据后管理患者。不久前的2017年,在比利时鲁汶的一次小型会议上,查尔斯-穆利根(Charles Mullighan)展示了总共264例T-ALL病例的转录组和WES数据。查尔斯的回答是:"当然。我们的研究才刚刚起步。我们相信,如果再问主要作者同样的问题,他们的回答很可能不会改变。黄一舟和Charles E. de Bock都得到了国家健康与医学研究委员会(NHMRC)Ideas Grant 2029411的资助。本出版物未获得任何资助。
{"title":"Overcoming a T-ALL order: A comprehensive study linking genomics to clinical outcomes","authors":"Yizhou Huang,&nbsp;Charles E. de Bock","doi":"10.1002/hem3.70027","DOIUrl":"https://doi.org/10.1002/hem3.70027","url":null,"abstract":"&lt;p&gt;Acute lymphoblastic leukemia (ALL) remains a leading success story of how modern therapies have improved patient outcomes from less than 10% survival rate in the 1950s to exceeding 90% today. This has been in part from the decades of research in the optimal use of chemotherapeutics, and, for B-cell ALL (B-ALL), the implementation of risk stratification based on clinical factors (e.g., age and peripheral blood cell counts), minimal/measurable residual disease (MRD), and cytogenetics (favorable, neutral, or unfavorable). However, for T-cell ALL (T-ALL), risk stratification is currently only based on MRD levels at the end of induction and again at the end of consolidation therapy with genomics and cytogenetics not considered prognostic factors in treatment decision-making.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; In an effort to include genomics into the risk stratification for T-ALL, a new study led by Charles Mullighan and David Teachey&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; has now been published as a landmark analysis of 1300 uniformly treated T-ALL cases that, for the first time, not only defines a total of 15 discrete genetic subtypes but also links them to clinical outcomes.&lt;/p&gt;&lt;p&gt;This new study integrates whole genome sequencing (WGS), whole exome sequencing (WES), and whole transcriptome sequencing data to expand the classification of T-ALL into a total of 15 different subtypes (Figure 1). The most significant variation from the current classification is the definition of two new subtypes, including a new early T-cell precursor (ETP)-like ALL subtype and an LMO2 γδ-like subtype—both of which have a diverse set of genetic alterations. Of the many genetic alterations, an interesting discriminator is the &lt;i&gt;KMT2A&lt;/i&gt; fusions present in the ETP-like subtype being mostly &lt;i&gt;KMT2A::AFDN&lt;/i&gt; fusion, while the non-ETP subtypes exclusively have &lt;i&gt;KMT2A::MLLT1&lt;/i&gt; fusion. The authors also compared the gene expression signatures of all 15 subtypes with normal hematopoietic and T-cell development cell stages. They found that the different T-ALL subtypes mapped across the entire continuum of T-cell development, supporting the hypothesis that each subtype represented a “frozen” stage of cellular differentiation. In the case of the ETP-like subtype, despite the heterogenous genetic drivers, the most likely cell of origin was found to be hematopoietic stem and progenitor cells (HSPC).&lt;/p&gt;&lt;p&gt;It will come as no surprise that this study confirms the high frequency of recurrent &lt;i&gt;NOTCH1&lt;/i&gt; mutations (69% of cases) in T-ALL, second only to &lt;i&gt;CDKN2A&lt;/i&gt; alterations (71% of cases), with the majority being coding sequence mutations that lead to activation of NOTCH1 signaling. However, this study also found rare single-nucleotide variants (SNV) within intron 28 of the &lt;i&gt;NOTCH1&lt;/i&gt; gene which generated a new splice acceptor site and resulted in a 43 amino acid insertion between the heterodimerization (HD) domain and the transmembrane (TM) domain of NOTCH1. Functionally, this new mutation","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435264","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
Outcomes and prognostic factors in 3306 patients with relapsed/refractory chronic lymphocytic leukemia treated with ibrutinib outside of clinical trials: A nationwide study 在临床试验之外接受伊布替尼治疗的 3306 例复发/难治性慢性淋巴细胞白血病患者的疗效和预后因素:一项全国性研究。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-08 DOI: 10.1002/hem3.70017
Gian Matteo Rigolin, Pier Paolo Olimpieri, Valentina Summa, Simone Celant, Lydia Scarfò, Maria Pia Ballardini, Antonio Urso, Silvia Gambara, Francesco Cavazzini, Paolo Ghia, Antonio Cuneo, Pierluigi Russo

We performed a cohort study that included all patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) who received ibrutinib in the Italian National Health Service. With a median follow-up of 42.2 months (IQR 30.8–54.6 months), the study involved 3306 patients with a median age of 72.1 years, of whom 42.6% had received ≥2 previous lines of treatment. The estimated 24-month probabilities of being on treatment and alive were 57.9% (95% confidence interval [CI]: 59.6–56.2) and 76.6% (95% CI: 75.2–78.1), respectively. The median time to treatment discontinuation (TTD) was 31.3 months (95% CI: 29.5–33.5). Out of 3306 patients, 2015 (60.9%) discontinued treatment, with 993 cases attributed to death or disease progression (30.0% of all cases). Among the 1022 patients who discontinued treatment for reasons other than progression or death, 564 (17.1%) patients did so due to toxicity or medical decision, while 458 patients (13.8%) were lost to follow-up. Multivariable analysis revealed that age, Eastern Cooperative Oncology Group Performance Status, the number of previous lines of therapy, refractoriness to the last treatment, and reduced renal function were associated with shorter TTD and overall survival (OS). The coexistence of 17p− and TP53 mutations had an independent unfavorable impact on TTD and OS. Nonstandard doses were associated with shorter TTD and advanced stage with shorter OS. The median OS postprogression and postdiscontinuation for other reasons were estimated at 12.9 (95% CI: 11.3–16.2) and 22.7 months (95% CI: 20.2–28.3), respectively. This large real-world study shows that ibrutinib is an effective treatment for R/R CLL. Baseline patient characteristics and double-hit TP53 aberrations were associated with inferior prognosis, and discontinuation due to CLL progression portended a poor outcome.

我们开展了一项队列研究,纳入了意大利国家医疗服务机构所有接受伊布替尼治疗的复发/难治性慢性淋巴细胞白血病(R/R CLL)患者。该研究的中位随访时间为 42.2 个月(IQR 30.8-54.6 个月),共涉及 3306 名患者,中位年龄为 72.1 岁,其中 42.6% 的患者曾接受过≥2 次治疗。估计24个月内接受治疗和存活的概率分别为57.9%(95%置信区间[CI]:59.6-56.2)和76.6%(95%置信区间:75.2-78.1)。停止治疗的中位时间(TTD)为 31.3 个月(95% 置信区间:29.5-33.5)。在 3306 例患者中,2015 例(60.9%)中止了治疗,其中 993 例是由于死亡或疾病进展(占所有病例的 30.0%)。在因病情进展或死亡以外的原因而中断治疗的 1022 例患者中,有 564 例(17.1%)患者是由于毒性或医疗决定而中断治疗,另有 458 例(13.8%)患者失去了随访机会。多变量分析显示,年龄、东部合作肿瘤学组(Eastern Cooperative Oncology Group)表现状态、既往治疗次数、对上次治疗的耐受性以及肾功能减退与较短的TTD和总生存期(OS)有关。17p基因突变和TP53基因突变同时存在对TTD和OS有不利影响。非标准剂量与较短的TTD有关,晚期与较短的OS有关。进展后和因其他原因停药后的中位OS估计分别为12.9个月(95% CI:11.3-16.2)和22.7个月(95% CI:20.2-28.3)。这项大型真实世界研究表明,伊布替尼是治疗R/R CLL的有效方法。基线患者特征和双击TP53畸变与不良预后有关,因CLL进展而停药预示着不良预后。
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引用次数: 0
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