Pub Date : 2024-11-05eCollection Date: 2024-11-01DOI: 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
{"title":"30-Minute infusion of isatuximab in patients with newly diagnosed multiple myeloma: Results of a Phase 1b study analysis.","authors":"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","doi":"10.1002/hem3.70041","DOIUrl":"10.1002/hem3.70041","url":null,"abstract":"","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590294","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}
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。
{"title":"GPRASP protein deficiency triggers lymphoproliferative disease by affecting B-cell differentiation","authors":"Antonio Morales-Hernández, Emilia Kooienga, Heather Sheppard, Gabriela Gheorghe, Claire Caprio, Ashley Chabot, Shannon McKinney-Freeman","doi":"10.1002/hem3.70037","DOIUrl":"10.1002/hem3.70037","url":null,"abstract":"<p><i>Gprasp1</i> and <i>Gprasp2</i> 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 <i>Gprasp1</i> and <i>Gprasp2</i>-deficient B-cells accumulate in the GC and show transcriptional abnormalities, affecting the mechanisms controlling <i>Aicda</i> expression and exposing them to excessive somatic hypermutation. Consequently, about 30% of mice transplanted with <i>Gprasp</i>-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 <i>Gprasp1-</i> and <i>Gprasp2-</i>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 <i>Gprasp1</i> and <i>Gprasp2</i> 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.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545088","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}
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。
{"title":"Mitochondrial retention in mature red blood cells from patients with sickle cell disease is associated with stress erythropoiesis but not with proinflammatory state","authors":"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","doi":"10.1002/hem3.70030","DOIUrl":"https://doi.org/10.1002/hem3.70030","url":null,"abstract":"<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.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142525355","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}
<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 <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":"<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","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}
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.
{"title":"Long-term outcome of 2-year survivors after allogeneic hematopoietic cell transplantation for acute leukemia","authors":"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","doi":"10.1002/hem3.70026","DOIUrl":"10.1002/hem3.70026","url":null,"abstract":"<p>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.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499347","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}
<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
{"title":"Casting light on the national mission to eliminate sickle cell disease in India","authors":"Frédéric B. Piel, Roshan Colah, Dipty L. Jain","doi":"10.1002/hem3.70033","DOIUrl":"https://doi.org/10.1002/hem3.70033","url":null,"abstract":"<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","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451778","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}
<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><
{"title":"Promoting and supporting leadership in hematology departments","authors":"Roch Houot, Emmanuel Gyan","doi":"10.1002/hem3.70028","DOIUrl":"https://doi.org/10.1002/hem3.70028","url":null,"abstract":"<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><","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}
<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
{"title":"Overcoming a T-ALL order: A comprehensive study linking genomics to clinical outcomes","authors":"Yizhou Huang, Charles E. de Bock","doi":"10.1002/hem3.70027","DOIUrl":"https://doi.org/10.1002/hem3.70027","url":null,"abstract":"<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","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}
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.
{"title":"Outcomes and prognostic factors in 3306 patients with relapsed/refractory chronic lymphocytic leukemia treated with ibrutinib outside of clinical trials: A nationwide study","authors":"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","doi":"10.1002/hem3.70017","DOIUrl":"10.1002/hem3.70017","url":null,"abstract":"<p>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 <i>TP53</i> 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 <i>TP53</i> aberrations were associated with inferior prognosis, and discontinuation due to CLL progression portended a poor outcome.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11459203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390135","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}