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How I Treat Older Patients with Ph/BCR-ABL-Negative Acute Lymphoblastic Leukemia. 我如何治疗 Ph/BCR-ABL 阴性急性淋巴细胞白血病老年患者?
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-11 DOI: 10.1182/blood.2023023156
Nicola Gökbuget, Björn Steffen

Despite advancements in new treatments, management of older patients with acute lymphoblastic leukaemia (ALL) remains an unmet medical need. With increasing age, ALL patients have a significantly lower CR rate, higher early mortality and relapse rate, and poorer survival compared to younger patients. This is attributed to a higher prevalence of adverse prognostic factors among older individuals and reduced tolerance to chemotherapy. Progress has been made in tailoring moderately intensive chemotherapy protocols for Ph/BCR-ABL (Ph) negative ALL in older patients, and recent phase II studies have explored integrating immunotherapy into initial treatment with very promising results. However, establishing new standard regimens for this age group remains and improving general management strategy is a pending task.

尽管新疗法取得了进展,但老年急性淋巴细胞白血病(ALL)患者的治疗仍是一项尚未满足的医疗需求。与年轻患者相比,随着年龄的增长,ALL 患者的 CR 率明显降低,早期死亡率和复发率较高,存活率较低。这归因于老年人中不良预后因素的发生率更高,以及对化疗的耐受性降低。针对老年患者Ph/BCR-ABL(Ph)阴性ALL的中度强化化疗方案的定制已取得进展,最近的II期研究还探索将免疫疗法纳入初始治疗,并取得了很好的效果。然而,为这一年龄组的患者制定新的标准方案以及改进一般管理策略仍是一项有待完成的任务。
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引用次数: 0
T-Cell Lymphomas in Recipients of CAR-T Cells: Assessing Risks and Causalities. CAR-T 细胞受体中的 T 细胞淋巴瘤:评估风险和因果关系。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-11 DOI: 10.1182/blood.2024025828
Jingqiong Hu, Cynthia E Dunbar

The United States Food and Drug Administration (FDA) announcement in November 2023 regarding reports of the occurrence of secondary T-cell lymphomas in patients receiving chimeric antigen receptor T-cells (CAR-T) for B-cell malignancies resulted in widespread concern among patients, clinicians and scientists. Little information relevant to assessing causality, most importantly whether CAR retroviral or lentiviral vector genomic insertions contribute to oncogenesis, was initially available. However, since that time several publications have provided clinical and molecular details on three cases showing clonal CAR vector insertions in tumor cells but without firm evidence these insertions played any role in oncogenic transformation. In addition, several other cases have been reported without vector detected in tumor cells. In addition, epidemiologic analyses as well as institutional long-term CAR-T recipient cohort studies provide important additional information suggesting the risk of T-cell lymphomas following CAR-T therapies is extremely low. This review will provide a summary of information available to date, as well as review relevant prior research suggesting a low susceptibility of mature T-cells to insertional oncogenesis and documenting the almost complete lack of T-cell transformation following natural HIV infection. Alternative factors that may predispose patients treated with CAR-T cells to secondary hematologic malignancies, including immune dysfunction and clonal hematopoiesis, are discussed and likely play a greater role than insertional mutagenesis in secondary malignancies post-CAR therapies.

美国食品和药物管理局(FDA)于 2023 年 11 月公布了关于接受嵌合抗原受体 T 细胞(CAR-T)治疗 B 细胞恶性肿瘤的患者出现继发性 T 细胞淋巴瘤的报告,引起了患者、临床医生和科学家的广泛关注。最初,与评估因果关系相关的信息很少,最重要的是 CAR 逆转录病毒或慢病毒载体基因组插入是否会导致肿瘤发生。不过,从那时起,一些出版物提供了三个病例的临床和分子细节,这些病例显示肿瘤细胞中有克隆性 CAR 载体插入,但没有确凿证据表明这些插入在致癌转化中起了任何作用。此外,还报道了其他几例肿瘤细胞中未检测到载体的病例。此外,流行病学分析以及机构长期 CAR-T 受体队列研究也提供了重要的补充信息,表明 CAR-T 疗法后发生 T 细胞淋巴瘤的风险极低。本综述将总结迄今为止的信息,并回顾之前的相关研究,这些研究表明成熟 T 细胞对插入性肿瘤发生的易感性很低,并记录了自然感染 HIV 后几乎完全没有 T 细胞转化的情况。报告还讨论了可能使接受 CAR-T 细胞治疗的患者易患继发性血液系统恶性肿瘤的其他因素,包括免疫功能障碍和克隆造血,这些因素在 CAR 疗法后继发性恶性肿瘤中的作用可能比插入突变更大。
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引用次数: 0
FISHing for clarity in double-hit lymphomas. 通过 FISH 检测,明确双重打击淋巴瘤。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2024026379
Stefan K Alig
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引用次数: 0
Molecular taxonomy of myelodysplastic syndromes and its clinical implications. 骨髓增生异常综合征的分子分类及其临床意义。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2023023727
Elsa Bernard, Robert P Hasserjian, Peter L Greenberg, Juan E Arango Ossa, Maria Creignou, Heinz Tuechler, Jesus Gutierrez-Abril, Dylan Domenico, Juan S Medina-Martinez, Max Levine, Konstantinos Liosis, Noushin Farnoud, Maria Sirenko, Martin Jädersten, Ulrich Germing, Guillermo Sanz, Arjan A van de Loosdrecht, Yasuhito Nannya, Olivier Kosmider, Matilde Y Follo, Felicitas Thol, Lurdes Zamora, Ronald F Pinheiro, Andrea Pellagatti, Harold K Elias, Detlef Haase, Christina Ganster, Lionel Ades, Magnus Tobiasson, Laura Palomo, Matteo Giovanni Della Porta, Pierre Fenaux, Monika Belickova, Michael R Savona, Virginia M Klimek, Fabio P S Santos, Jacqueline Boultwood, Ioannis Kotsianidis, Valeria Santini, Francesc Solé, Uwe Platzbecker, Michael Heuser, Peter Valent, Carlo Finelli, Maria Teresa Voso, Lee-Yung Shih, Michaela Fontenay, Joop H Jansen, José Cervera, Norbert Gattermann, Benjamin L Ebert, Rafael Bejar, Luca Malcovati, Seishi Ogawa, Mario Cazzola, Eva Hellström-Lindberg, Elli Papaemmanuil

Abstract: Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. Although genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations, and copy-neutral loss of heterozygosity were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91%, 43%, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and loss of heterozygosity at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow (BM) blast percentage across groups ranged from 1.5% to 10%, and the median overall survival ranged from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of BM blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and might inform future classification schemas and translational therapeutic research.

骨髓增生异常综合征/肿瘤(MDS)是以骨髓细胞形态异常和外周细胞减少为特征的克隆性血液病。虽然遗传异常是这些疾病发病机制及其异质性的基础,但目前 MDS 的分类主要依赖于形态学。我们对 3233 名 MDS 或相关疾病患者进行了基因组分析,以划分分子亚型并确定其临床意义。基因突变、拷贝数改变(CNA)和拷贝中性杂合性缺失(cnLOH)是通过对 152 个基因进行靶向测序得出的,分别在 91%、43% 和 11% 的患者中发现了异常。我们利用 21 个基因、6 个细胞遗传学事件以及 TP53 和 TET2 基因座的 LOH 信息,确定了 16 个分子组别,涵盖了 86% 的患者。根据阴性结果(分子上未作其他说明、无复发驱动因素)定义的两个残留组占患者总数的14%。这两组患者的比例从 0.5% 到 14% 不等,并与不同的临床表型和预后相关。各组的中位骨髓爆破率从 1.5% 到 10% 不等,中位总生存期从 0.9 年到 8.2 年不等。我们验证了 5 个特征明确的实体,为 3 个之前报道的亚组提供了进一步的证据支持,并描述了 8 个新的组别。骨髓囊泡对预后的影响取决于基因亚型。在基因亚群中,与治疗相关的MDS和骨髓增生异常/骨髓增生性肿瘤(MDS/MPN)的临床和预后情况与原发性MDS相当。总之,MDS 的基因亚群与临床相关,可为未来的分类模式和转化治疗研究提供参考。
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引用次数: 0
Breaking T-cell tolerance in the immune system. 打破免疫系统中的 T 细胞耐受性
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2024026075
Jin Y Chen
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引用次数: 0
Genetic medicine gestating for α-thalassemia. 遗传医学妊娠α地中海贫血症。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2024025938
Daniel E Bauer
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引用次数: 0
Mitigation of checkpoint inhibitor-induced autoimmune hemolytic anemia through modulation of purinergic signaling. 通过调节嘌呤能信号缓解检查点抑制剂诱发的自身免疫性溶血性贫血
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2024024230
Flavia Dei Zotti, Annie Qiu, Vivette D D'Agati, Shwatina Jagnarine, Emmalene Kyritsis, Anabel Miller, Maria Tredicine, Daysha Fliginger, Elizabeth F Stone, Sandhya Panch, Krystalyn E Hudson

Abstract: Immune checkpoint inhibitors (ICPis) have revolutionized cancer immunotherapy but also can induce autoimmune hemolytic anemia (AIHA), a severe disease with high mortality. However, the cellular and molecular mechanism(s) of AIHA secondary to ICPi therapy (ICPi-AIHA) are unclear, other than being initiated through decreased checkpoint inhibition. Herein, we report ICPi-AIHA in a novel mouse model that shows similar characteristics of known human ICPi-AIHA (eg, autoantibodies, hemolysis, and increased mortality). During ICPi-AIHA, there is the simultaneous reduction of 2 regulatory T-cell populations (FoxP3+ and Tr1 [type 1 regulatory cells]) and an increase in inflammatory T helper cell 17 (TH17). Moreover, a novel CD39+CD73-FoxP3-CD25- CD4+ T-cell subset (ie, CD39 single positive [CD39SP]) emerges, and early increases in CD39SP predict AIHA development; CD39 is an ectonuclease that breaks down adenosine triphosphate (ATP). Additionally, we found that boosting ATPase activity by injecting recombinant apyrase mitigates AIHA development and significant CD39SP reductions, both suggesting a functional role for CD39 and demonstrating a novel therapeutic approach. Importantly, CD39SP are detectable in multiple mouse models developing AIHA and in patients with AIHA, demonstrating applicability to idiopathic and secondary AIHA. Highlighting broader autoimmunity relevance, ICPi-treated NZB mice experienced accelerated onset and severity of lupus, including AIHA. Moreover, ICPi treatment of healthy B6 animals led to detectable CD39SP and development of autoantibodies against multiple autoantigens including those on red blood cells and platelets. Together, our findings provide further insight into the cellular and molecular mechanisms of ICPi-AIHA, leading to novel diagnostic and therapeutic approaches with translational potential for use in humans being treated with ICPi.

免疫检查点抑制剂(ICPi)彻底改变了癌症免疫疗法,但也会诱发自身免疫性溶血性贫血(AIHA),这是一种死亡率很高的严重疾病。然而,ICPi-AIHA 的细胞和分子机制尚不清楚,只是通过减少检查点抑制而启动。在此,我们报告了一种新型小鼠ICPi-AIHA模型,该模型显示出与已知人类ICPi-AIHA相似的特征(如自身抗体、溶血、死亡率升高)。在ICPi-AIHA期间,两种调节性T细胞群(FoxP3+和Tr1 Tregs)同时减少,炎性TH17 T细胞增加。此外,还出现了一种新的 CD39+CD73-FoxP3-CD25- CD4+ T 细胞亚群(即 CD39 单阳性 [CD39SP]),CD39SP 的早期增加预示着 AIHA 的发展;CD39 是一种外切酶,能分解 ATP。此外,我们还发现,通过注射重组apyrase来增强ATP酶的活性可以缓解AIHA的发展和CD39SP的显著减少,这既表明了CD39的功能性作用,也展示了一种新的治疗方法。重要的是,CD39SP可在多种发生AIHA的小鼠模型和AIHA患者体内检测到,这表明它适用于特发性和继发性AIHA。ICPi处理的NZB小鼠会加速狼疮(包括AIHA)的发病和严重程度,这凸显了更广泛的自身免疫相关性。此外,ICPi 治疗健康的 B6 动物可检测到 CD39SP 和针对多种自身抗原(包括红细胞和血小板上的抗原)的自身抗体。总之,我们的研究结果阐明了ICPi-AIHA的细胞和分子机制,从而提出了新的诊断和治疗方法,并有望应用于接受ICPi治疗的人类。
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引用次数: 0
Tai Y-T, Fulciniti M, Hideshima T, Song W, Leiba M, Li X-F, Rumizen M, Burger P, Morrison A, Podar K, Chauhan D, Tassone P, Richardson P, Munshi NC, Ghobrial IM, Anderson KC. Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis. Blood. 2007;110(5):1656-1663. 110(5)1656 Tai retraction.
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2024026818

This article has been retracted; please see Elsevier's Article Correction, Retraction and Removal Policy (Article withdrawal | Elsevier policy).This article has been retracted at the request of the Editors and authors.Within the paper, image issues were identified in Figures 1, 4, and 6. Images within these figures show duplication, modification, or unmarked splices.The authors state that these figures cannot be used to support the conclusions of the paper.Authors Tai, Fulciniti, Song, Li, Morrison, Chauhan, Tassone, Ghobrial, and Anderson approve the retraction. Authors Hideshima, Leiba, Rumizen, Burger, Podar, Richardson, and Munshi did not respond.

本文已被撤稿;请参阅爱思唯尔的文章更正、撤稿和删除政策(文章撤稿 | 爱思唯尔政策)。应编辑和作者的要求,本文已被撤稿。这些图中的图像显示了重复、修改或未标记的拼接。作者声明,这些图不能用来支持论文的结论。作者 Tai、Fulciniti、Song、Li、Morrison、Chauhan、Tassone、Ghobrial 和 Anderson 同意撤稿。作者 Hideshima、Leiba、Rumizen、Burger、Podar、Richardson 和 Munshi 没有回应。
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引用次数: 0
Seeing MDS through the lens of genomics. 从基因组学的角度看 MDS。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2024025676
Lachlin Vaughan, John E Pimanda
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引用次数: 0
Unbalanced MYC break-apart FISH patterns indicate the presence of a MYC rearrangement in HGBCL-DH-BCL2. 不平衡的 MYC 分裂 FISH 模式表明 HGBCL-DH-BCL2 中存在 MYC 重排。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-10 DOI: 10.1182/blood.2024025603
Brett Collinge, Susana Ben-Neriah, Laura K Hilton, Waleed Alduaij, Tracy Tucker, Graham W Slack, Pedro Farinha, Jeffrey W Craig, Merrill Boyle, Barbara Meissner, Diego Villa, Alina S Gerrie, Laurie H Sehn, Kerry J Savage, Ryan D Morin, Andrew J Mungall, Christian Steidl, David W Scott

Abstract: Fluorescence in situ hybridization (FISH) using break-apart probes is recommended for identifying high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2). Unbalanced MYC break-apart patterns, in which the red or green signal is lost, are commonly reported as an equivocal result by clinical laboratories. In a cohort of 297 HGBCL-DH-BCL2, 13% of tumors had unbalanced MYC break-apart patterns with loss of red (LR; 2%) or loss of green (LG; 11%) signal. To determine the significance of these patterns, MYC rearrangements were characterized by sequencing in 130 HGBCL-DH-BCL2, including 3 LR and 14 LG tumors. A MYC rearrangement was identified for 71% of tumors with LR or LG patterns, with the majority involving immunoglobulin loci or other recurrent MYC rearrangement partners. The architecture of these rearrangements consistently preserved the rearranged MYC allele, with the MYC gene predicted to be on the derivative chromosome containing the signal that is still present in nearly all cases. MYC protein expression, MYC messenger RNA expression, and the proportion of tumors expressing the dark-zone signature was not significantly different between balanced and unbalanced groups. These results support a recommendation that unbalanced MYC break-apart FISH patterns be reported as positive for MYC rearrangement in the context of diagnosing HGBCL-DH-BCL2.

建议使用断裂探针进行荧光原位杂交(FISH),以鉴别伴有MYC和BCL2重排的高级别B细胞淋巴瘤(HGBCL-DH-BCL2)。不平衡的 MYC 分裂模式(红色或绿色信号消失)通常被临床实验室报告为不确定的结果。在一组 297 例 HGBCL-DH-BCL2 肿瘤中,13% 的肿瘤具有不平衡的 MYC 分裂模式,红色(LR:2%)或绿色(LG:11%)信号丢失。为了确定这些模式的意义,对 130 例 HGBCL-DH-BCL2 肿瘤(包括 3 例 LR 肿瘤和 14 例 LG 肿瘤)的 MYC 重排进行了测序定性。71%具有LR或LG模式的肿瘤中发现了MYC重排,其中大部分涉及免疫球蛋白位点或其他复发性MYC重排伙伴。这些重排的结构一致保留了重排的 MYC 等位基因,据预测,MYC 基因位于含有信号的衍生染色体上,而信号几乎在所有病例中都仍然存在。平衡组和非平衡组的 MYC 蛋白表达、MYC mRNA 表达以及表达暗区特征的肿瘤比例没有显著差异。这些结果支持一项建议,即在诊断 HGBCL-DH-BCL2 时,将不平衡的 MYC 分裂 FISH 模式报告为 MYC 重排阳性。
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引用次数: 0
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