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First-line ibrutinib treatment in patients with chronic lymphocytic leukemia is associated with overall survival rates similar to those of an age-matched general population: A pooled post hoc analysis 慢性淋巴细胞白血病患者接受伊布替尼一线治疗后的总生存率与年龄匹配的普通人群相似:汇总事后分析
IF 6.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-05-27 DOI: 10.1002/hem3.74
Paolo Ghia, Carolyn Owen, John N. Allan, Jacqueline C. Barrientos, Paul M. Barr, Chunxue Shi, Anita Szoke, Christopher Abbazio, Gabriel S. Krigsfeld, Jan A. Burger
<p>Currently, there are no targeted agents that can cure chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), which is the most common leukemia among older adults.<span><sup>1</sup></span> In the absence of a curative regimen, the therapeutic goal is to maximize patients' life span while effectively managing disease symptoms.</p><p>Ibrutinib, a covalent, once-daily Bruton's tyrosine kinase inhibitor, has been shown to have survival superiority to chemotherapy (CT) and chemoimmunotherapy (CIT) in the first-line setting, including older adults and those with high-risk characteristics, and has demonstrated overall survival (OS) improvements in multiple pivotal trials.<span><sup>2-4</sup></span> In a long-term follow-up from RESONATE-2 of up to 8 years, first-line treatment with ibrutinib was associated with superior progression-free survival and OS compared with standard-of-care CT. Based on the results from the same study, adverse events (AEs) associated with ibrutinib can be managed effectively with dose reductions or dose holds, which results in AE resolution in most patients (85% and 90%, respectively), allowing them to remain on treatment and continue benefiting from ibrutinib.<span><sup>5</sup></span> The relatively long survival of patients with CLL/SLL treated with ibrutinib raises the question of whether the initiation of first-line ibrutinib could remove the survival hazard associated with CLL/SLL compared with the general population. The aims of this pooled analysis were to compare OS estimates of previously untreated patients with CLL/SLL who received ibrutinib or CT/CIT across three phase 3 studies with the OS estimates for an age-matched general population.</p><p>This post hoc analysis included data pooled from three randomized (1:1) controlled studies in patients with previously untreated CLL/SLL: RESONATE-2 (NCT01722487),<span><sup>2</sup></span> iLLUMINATE (NCT02264574),<span><sup>4</sup></span> and ECOG-ACRIN E1912 (NCT02048813).<span><sup>3</sup></span> Patients were separated into two groups: ibrutinib cohort (patients treated with ibrutinib, ibrutinib with rituximab, or ibrutinib with obinutuzumab); and CT/CIT cohort (patients receiving rituximab plus fludarabine plus cyclophosphamide, chlorambucil plus obinutuzumab, or single-agent chlorambucil). Details of the treatments and populations have been previously published for each study, and brief descriptions are included in the Supporting Information.</p><p>OS data from the time of initial CLL/SLL diagnosis for the ibrutinib-treated cohort or CT/CIT-treated cohort were compared with survival estimates for an age-matched US population in 2019 published by the Centers for Disease Control and Prevention (CDC).<span><sup>6</sup></span> Age-matched (1:1 match) simulated databases were generated based on the age distribution of patients treated with ibrutinib or CT/CIT from the three phase 3 clinical studies. OS probabilities were estimated using the Kaplan–Meier methodol
慢性淋巴细胞白血病/小淋巴细胞淋巴瘤(CLL/SLL)是老年人中最常见的白血病,目前还没有靶向药物可以治愈慢性淋巴细胞白血病/小淋巴细胞淋巴瘤。伊布替尼是一种共价、每日一次的布鲁顿酪氨酸激酶抑制剂,在一线治疗(包括老年人和高危人群)中,其生存期优于化疗(CT)和化学免疫疗法(CIT),并在多项关键性试验中证明其总生存期(OS)有所改善。在RESONATE-2长达8年的长期随访中,伊布替尼一线治疗的无进展生存期和OS均优于标准治疗CT。根据同一研究的结果,与伊布替尼相关的不良反应(AEs)可通过减少剂量或暂停剂量得到有效控制,从而使大多数患者(分别为 85% 和 90%)的不良反应得到缓解,使他们能够继续接受治疗并继续从伊布替尼中获益。这项汇总分析的目的是将三项三期研究中接受伊布替尼或CT/CIT治疗的既往未接受治疗的CLL/SLL患者的OS估计值与年龄匹配的普通人群的OS估计值进行比较。这项事后分析汇总了三项针对既往未接受过治疗的 CLL/SLL 患者的随机(1:1)对照研究数据:RESONATE-2 (NCT01722487)、2 iLLUMINATE (NCT02264574)4 和 ECOG-ACRIN E1912 (NCT02048813)。3 患者分为两组:伊布替尼队列(接受伊布替尼、伊布替尼联合利妥昔单抗或伊布替尼联合奥比妥珠单抗治疗的患者);CT/CIT队列(接受利妥昔单抗联合氟达拉滨联合环磷酰胺、氯布嘧啶联合奥比妥珠单抗或单药氯布嘧啶治疗的患者)。伊布替尼治疗队列或CT/CIT治疗队列自初次诊断CLL/SLL时的OS数据与美国疾病控制和预防中心(CDC)发布的2019年美国年龄匹配人群的生存估计值进行了比较。6 根据三项三期临床研究中接受伊布替尼或 CT/CIT 治疗的患者年龄分布生成了年龄匹配(1:1 匹配)的模拟数据库。采用 Kaplan-Meier 方法估算 OS 概率。对基于伊布替尼疗法的安全性数据进行了评估,该数据来自RESONATE-2和iLLUMINATE患者的集合安全性人群。由于AE数据收集细节的限制,ECOG-ACRIN E1912研究的参与者未纳入安全性评估。关于研究设计和方法的更多信息请参见佐证资料。在三项试验的汇总样本中,603名患者接受了伊布替尼一线治疗,424名患者接受了CT/CIT治疗(表1)。接受伊布替尼治疗的患者随机分组时的中位年龄为63岁。大多数患者为男性(65%),东部合作肿瘤学组(ECOG)表现状态评分为0(57%),累积病情评分量表(CIRS)评分≤6(80%)。CT/CIT队列的基线特征相似(随机化时的中位年龄为67岁;男性占66%;ECOG表现状态评分为0分的占50%;CIRS评分≤6分的占76%)。表1列出了其他基线临床特征,包括基因检测结果。在伊布替尼治疗队列中,自随机化时起的中位治疗时间和中位随访时间分别为39个月和41个月;在CT/CIT治疗队列中,这两个时间分别为5个月和40个月(表S1)。伊布替尼治疗队列从最初诊断出CLL/SLL开始的中位随访时间为5.9年。伊布替尼治疗队列从最初诊断出CLL/SLL开始计算的OS与年龄匹配的普通人群的OS估计值相当(危险比[HR];95%置信区间[CI] = 0.87 [0.63-1.19])。伊布替尼治疗队列(82% [76-87])与年龄匹配的普通人群(80% [76-83])的12年OS估计值(95% CI)也相似(图1A)。相反,CT/CIT队列的OS显著低于(P = 0.05)年龄匹配的普通人群(HR [95% CI] = 1.35 [1.00-1. 在RESONATE-2和iLLUMINATE研究的248例可评估患者中,有48例(19%)从每天420毫克的起始剂量开始减少剂量以控制AEs(表S3)。伊布替尼减量治疗的中位持续时间为31个月(范围:0-84+)。减少伊布替尼剂量后,48 例患者中有 44 例(92%)的初始 AE 消失,48 例患者中有 32 例(67%)的 AE 不再复发或以较低的等级复发。在出现最近更新的美国处方信息中建议减少剂量的 AE 后,248 例患者中有 21 例(9%)减少了剂量(表 S4)。7其中,21例患者中有20例(95%)的初始AE得到缓解,21例患者中有16例(76%)的AE没有复发或复发等级较低。248例患者中有143例(58%)的AE处理采用了伊布替尼剂量暂停≥7天的方法(表S5)。248例患者中有118例(48%)在剂量维持≥7天后重新开始服用伊布替尼,剂量为420毫克;248例患者中有35例(14%)重新开始服用伊布替尼,剂量为280毫克;248例患者中有15例(6%)重新开始服用伊布替尼,剂量为140毫克。导致减量和停药≥7 天的 AEs 发生率在伊布替尼开始治疗后的头 2 年最高,随后几年有所下降(图 S2A 和 S2B)。自从引入 CLL/SLL 靶向疗法以来,与之前的标准疗法相比,伊布替尼显著改善了广大 CLL/SLL 患者的治疗效果,这已在多项随机临床试验中得到证实、3、8-11 在布鲁顿的酪氨酸激酶抑制剂疗法中,伊布替尼的随访时间最长,这为评估长期疗效和安全性提供了独特的条件。维持患者的治疗似乎对最大限度地提高临床疗效(包括延长生存期)至关重要,有些患者接受治疗的时间长达 8 年。对于RESONATE-2研究中的大多数患者来说,长期持续接受伊布替尼治疗是可能的,同时还可以通过积极的剂量管理来控制相关副作用。同样,在本汇总分析中,大多数患者在减量后 AE 消失,从而能够继续接受伊布替尼治疗。在本汇总分析中,伊布替尼一线 3 期试验中因 AE 而中断治疗的比例相似:在 RESONATE-2 中,24%5 的患者因 AE 而中断伊布替尼治疗;在 iLLUMINATE 中,16%13 的患者因 AE 而中断治疗;在 ECOG1912 中,22%的患者因 AE 而中断治疗。14 总体而言,该分析的安全性结果与之前描述的伊布替尼一线治疗的安全性特征一致,也与个别 3 期试验的数据一致、4、15 本研究的优点包括患者人数相对较多以及三项合并研究的随访时间较长。一项关键的局限性在于,由于数据的可用性,伊布替尼的汇总数据与普通人群的生存率估计值仅在年龄上进行了匹配,而未在其他患者个体特征上进行匹配。总之,这项事后分析表明,与一线CT/CIT治疗不同,一线伊布替尼的生存率与年龄匹配的普通人群的生存率相似。保罗-吉亚、约翰-N-阿兰、克里斯托弗-阿巴齐奥和加布里埃尔-S-克里格斯菲尔德构思了这项研究。Christopher Abbazio和Gabriel S. Krigsfeld设计了研究方法。施春雪进行了研究验证和统计分析。施春雪、加布里埃尔-S-克里格斯菲尔德和克里斯托弗-阿巴齐奥解释数据。Paolo Ghia、Carolyn Owen、John N. Allan、Jacqueline C. Barrientos、Paul M. Barr 和 Jan A. Burger 参与了数据采集/收集工作。所有作者都参与了稿件的撰写和审阅。P. G.从艾伯维、阿斯利康、BeiGene、百时美施贵宝、杨森、Loxo@Lilly、默沙东和罗氏
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引用次数: 0
Remission after CAR T-cell therapy: Do lymphoma patients recover a normal life? CAR T 细胞疗法后的缓解:淋巴瘤患者能否恢复正常生活?
IF 6.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-05-27 DOI: 10.1002/hem3.72
Alya Perthus, Fanny Colin, Emilie Charton, Amélie Anota, Faustine Lhomme, Guillaume Manson, Sophie De Guibert, Pierre Daufresne, Adeline Bellec, Laetitia Le Bars, Sandra De Barros, Loïc Ysebaert, Marianne Merceur, Mélanie Cogné, Thierry Lamy De La Chapelle, Roch Houot, Aline Moignet

Chimeric antigen receptor T cells (CAR T cells) can induce prolonged remission in a substantial subset of patients with relapse/refractory lymphoma. However, little is known about patients' life after CAR T-cell therapy. We prospectively assessed the multidimensional recovery of lymphoma patients in remission, before leukapheresis, before CAR T-cell infusion, and 3, 6, and 12 months thereafter. Validated tools were used to measure lymphoma-related and global health-related quality of life (HRQoL; Functional Assessment of Cancer Therapy-Lymphoma [FACT-Lym] and EQ-5D-5L), cognitive complaint (FACT-Cognition), fatigue (FACIT-Fatigue subscale), psychological status (Hospital Anxiety and Depression Scale, Post-Traumatic Check List Scale), and sexuality (Relationship and Sexuality Scale). Beyond 12 months of remission, we also surveyed physical, professional, sexual, and general life status. At 3, 6, and 12 months, 53, 35, and 23 patients were evaluable, respectively. Improvement in lymphoma-related HRQoL was clinically relevant at 3, 6, and 12 months with a mean change from baseline of 10.9 (95% confidence interval [CI]: 5.8; 16.1), 12.2 (95% CI: 4.2; 20.1), and 11.72 (95% CI: 2.06; 21.38), respectively. Improvement in global HRQoL, fatigue, and anxiety was clinically relevant, but 20%–40% of patients experienced persistent fatigue, psychological distress, and cognitive complaints over time. Beyond 12 months after CAR T cells, 81.8% of 22 evaluable patients were satisfied with their daily life. Physical activity, professional, sexual, and global well-being had returned to prediagnosis levels in nearly half of the patients. We found an improvement in HRQoL after CAR T-cell therapy including anxiety, depression, sexual satisfaction, and general well-being. However, not all patients recover a “normal life.” Further research is needed to determine which patients are at risk of quality-of-life impairment to improve recovery after CAR T-cell infusion.

嵌合抗原受体 T 细胞(CAR T 细胞)可诱导相当一部分复发/难治性淋巴瘤患者延长缓解期。然而,人们对 CAR T 细胞治疗后患者的生活知之甚少。我们对处于缓解期的淋巴瘤患者在白细胞清除术前、CAR T 细胞输注前及其后 3、6 和 12 个月的多维康复情况进行了前瞻性评估。采用经过验证的工具来测量淋巴瘤相关和整体健康相关生活质量(HRQoL;癌症治疗功能评估-淋巴瘤[FACT-Lym]和EQ-5D-5L)、认知症状(FACT-认知)、疲劳(FACIT-疲劳分量表)、心理状态(医院焦虑和抑郁量表、创伤后核对表量表)以及性能力(人际关系和性能力量表)。在缓解期满 12 个月后,我们还对身体、职业、性和一般生活状况进行了调查。在 3 个月、6 个月和 12 个月时,分别有 53 名、35 名和 23 名患者接受了评估。在 3、6 和 12 个月时,淋巴瘤相关 HRQoL 的改善与临床相关,与基线相比的平均变化分别为 10.9(95% 置信区间 [CI]:5.8;16.1)、12.2(95% CI:4.2;20.1)和 11.72(95% CI:2.06;21.38)。总体 HRQoL、疲劳和焦虑的改善与临床相关,但随着时间的推移,20%-40% 的患者会出现持续疲劳、心理困扰和认知抱怨。CAR T 细胞治疗 12 个月后,22 名可评估患者中有 81.8% 对自己的日常生活感到满意。近一半的患者在体育活动、职业、性生活和整体健康方面恢复到了诊断前的水平。我们发现,CAR T 细胞治疗后,患者的 HRQoL 有所改善,包括焦虑、抑郁、性满意度和总体幸福感。然而,并非所有患者都能恢复 "正常生活"。需要进一步研究确定哪些患者有生活质量受损的风险,以改善CAR T细胞输注后的恢复情况。
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引用次数: 0
Influence of donor–recipient sex on engraftment of normal and leukemia stem cells in xenotransplantation 异种移植中供体和受体性别对正常干细胞和白血病干细胞移植的影响
IF 6.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-05-21 DOI: 10.1002/hem3.80
Syed A. Mian, Linda Ariza-McNaughton, Fernando Anjos-Afonso, Remisha Guring, Sophie Jackson, Aytug Kizilors, John Gribben, Dominique Bonnet

Immunodeficient mouse models are widely used for the assessment of human normal and leukemic stem cells. Despite the advancements over the years, reproducibility, as well as the differences in the engraftment of human cells in recipient mice remains to be fully resolved. Here, we used various immunodeficient mouse models to characterize the effect of donor–recipient sex on the engraftment of the human leukemic and healthy cells. Donor human cells and recipient immunodeficient mice demonstrate sex-specific engraftment levels with significant differences observed in the lineage output of normal CD34+ hematopoietic stem and progenitor cells upon xenotransplantation. Intriguingly, human female donor cells display heightened sensitivity to the recipient mice's gender, influencing their proliferation and resulting in significantly increased engraftment in female recipient mice. Our study underscores the intricate interplay taking place between donor and recipient characteristics, shedding light on important considerations for future studies, particularly in the context of pre-clinical research.

免疫缺陷小鼠模型被广泛用于评估人类正常干细胞和白血病干细胞。尽管多年来取得了进步,但人类细胞在受体小鼠体内移植的可重复性和差异仍有待完全解决。在这里,我们使用各种免疫缺陷小鼠模型来描述供体-受体性别对人类白血病细胞和健康细胞移植的影响。人类供体细胞和受体免疫缺陷小鼠显示出性别特异性的移植水平,异种移植后正常 CD34+ 造血干细胞和祖细胞的系输出存在显著差异。耐人寻味的是,人类雌性供体细胞对受体小鼠的性别显示出更高的敏感性,从而影响其增殖,并导致雌性受体小鼠的接种率显著增加。我们的研究强调了供体和受体特征之间错综复杂的相互作用,为今后的研究,尤其是临床前研究提供了重要的参考。
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引用次数: 0
Toward a more patient-centered drug development process in clinical trials for patients with myelodysplastic syndromes/neoplasms (MDS): Practical considerations from the International Consortium for MDS (icMDS) 在针对骨髓增生异常综合征/肿瘤(MDS)患者的临床试验中采用更加以患者为中心的药物开发流程:国际骨髓增生异常综合征联盟(icMDS)的实际考虑因素
IF 6.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-05-21 DOI: 10.1002/hem3.69
Fabio Efficace, Rena Buckstein, Gregory A. Abel, Johannes M. Giesinger, Pierre Fenaux, Jan Philipp Bewersdorf, Andrew M. Brunner, Rafael Bejar, Uma Borate, Amy E. DeZern, Peter Greenberg, Gail J. Roboz, Michael R. Savona, Francesco Sparano, Jacqueline Boultwood, Rami Komrokji, David A. Sallman, Zhuoer Xie, Guillermo Sanz, Hetty E. Carraway, Justin Taylor, Stephen D. Nimer, Matteo Giovanni Della Porta, Valeria Santini, Maximilian Stahl, Uwe Platzbecker, Mikkael A. Sekeres, Amer M. Zeidan

Notable treatment advances have been made in recent years for patients with myelodysplastic syndromes/neoplasms (MDS), and several new drugs are under development. For example, the emerging availability of oral MDS therapies holds the promise of improving patients' health-related quality of life (HRQoL). Within this rapidly evolving landscape, the inclusion of HRQoL and other patient-reported outcomes (PROs) is critical to inform the benefit/risk assessment of new therapies or to assess whether patients live longer and better, for what will likely remain a largely incurable disease. We provide practical considerations to support investigators in generating high-quality PRO data in future MDS trials. We first describe several challenges that are to be thoughtfully considered when designing an MDS-focused clinical trial with a PRO endpoint. We then discuss aspects related to the design of the study, including PRO assessment strategies. We also discuss statistical approaches illustrating the potential value of time-to-event analyses and their implications within the estimand framework. Finally, based on a literature review of MDS randomized controlled trials with a PRO endpoint, we note the PRO items that deserve special attention when reporting future MDS trial results. We hope these practical considerations will facilitate the generation of rigorous PRO data that can robustly inform MDS patient care and support treatment decision-making for this patient population.

近年来,骨髓增生异常综合征/肿瘤(MDS)患者的治疗取得了显著进展,一些新药正在研发中。例如,新出现的口服 MDS 疗法有望改善患者的健康相关生活质量(HRQoL)。在这种快速发展的形势下,纳入 HRQoL 和其他患者报告的结果 (PROs) 对于新疗法的获益/风险评估或评估患者是否活得更长、活得更好至关重要,因为这种疾病很可能在很大程度上仍是一种不治之症。我们提供了一些实用的注意事项,以支持研究者在未来的 MDS 试验中生成高质量的 PRO 数据。我们首先介绍了在设计以 PRO 为终点的 MDS 临床试验时需要深思熟虑的几个挑战。然后,我们讨论了与研究设计相关的方面,包括 PRO 评估策略。我们还讨论了说明时间到事件分析潜在价值的统计方法及其在估计值框架内的影响。最后,根据对以 PRO 为终点的 MDS 随机对照试验的文献回顾,我们指出了在报告未来 MDS 试验结果时值得特别关注的 PRO 项目。我们希望这些实用的考虑因素将有助于生成严格的 PRO 数据,从而为 MDS 患者的护理提供可靠的信息,并为该患者群体的治疗决策提供支持。
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引用次数: 0
An integrated classification of tumor suppressor IKZF1 inactivation and oncogenic activation in Philadelphia chromosome-like acute lymphoblastic leukemia 费城染色体样急性淋巴细胞白血病中肿瘤抑制因子 IKZF1 失活和致癌激活的综合分类
IF 6.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-05-21 DOI: 10.1002/hem3.82
Zicong Huang, Ling Zhang, Xiaoyuan Gong, Jia Li, Shiyu Deng, Zihong Cai, Bingqing Tang, Kangyu Huang, Xin Li, Weihua Zhao, Yang Xu, Li Xuan, Qifa Liu, Ying Wang, Suning Chen, Hongsheng Zhou

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is recognized for its genetic and clinical diversity. In this study, we identified a novel high-risk subset of Ph-like ALL, characterized by the activation of oncogenic signaling and the inactivation of the tumor suppressor gene IKZF1, resulting in a dismal outcome. The association between cytogenetic aberrations and clinical features was assessed on a cohort of 191 patients with Ph-like ALL. Our findings revealed that patients with inactivation of IKZF1 combined with activation of oncogenic signaling (CRLF2/EPOR/JAK2 rearrangements or p-CRKL/p-STAT5 high expression) had the worst outcome (3-year overall survival [OS] of 28.8% vs. 80.1% for others, p < 0.001; 2-year event-free survival [EFS] of 6.5% vs. 57.0% for others, p < 0.001). Multivariable analysis demonstrated that this high-risk feature was an independent inferior prognostic factor (adjusted hazard ratio for OS = 4.55, 95% confidence interval [CI]: 2.35–8.81, p < 0.001; adjusted hazard ratio for EFS = 3.27, 95% CI: 1.99–5.39, p < 0.001). Allogeneic hematopoietic stem cell transplantation was associated with improved prognoses in patients within the high-risk subgroup. In conclusion, this study identified a clinically distinct entity that possesses effective prognostic features and provides potential guidance for refining risk stratification in Ph-like ALL.

费城染色体(Ph)样急性淋巴细胞白血病(ALL)具有遗传和临床多样性。在这项研究中,我们发现了一个新的费城染色体样急性淋巴细胞白血病高危亚群,其特征是致癌信号的激活和抑癌基因IKZF1的失活,导致了不良的预后。我们对191例Ph样ALL患者的细胞遗传学畸变与临床特征之间的关系进行了评估。我们的研究结果显示,IKZF1失活合并致癌信号激活(CRLF2/EPOR/JAK2重排或p-CRKL/p-STAT5高表达)的患者预后最差(3年总生存率[OS]为28.8%,其他患者为80.1%,p <0.001;2年无事件生存率[EFS]为6.5%,其他患者为57.0%,p <0.001)。多变量分析表明,这一高风险特征是一个独立的不良预后因素(调整后的 OS 危险比 = 4.55,95% 置信区间 [CI]:2.35-8.81,p < 0.001;调整后的 EFS 危险比 = 3.27,95% CI:1.99-5.39,p < 0.001)。异体造血干细胞移植与高风险亚组患者预后的改善有关。总之,这项研究发现了一个临床上独特的实体,它具有有效的预后特征,并为完善Ph-like ALL的风险分层提供了潜在的指导。
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引用次数: 0
Treatment outcomes in patients with large B-cell lymphoma after progression to chimeric antigen receptor T-cell therapy 大 B 细胞淋巴瘤患者接受嵌合抗原受体 T 细胞疗法后的治疗结果
IF 6.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-05-21 DOI: 10.1002/hem3.62
Gloria Iacoboni, Josu Iraola-Truchuelo, Maeve O'Reilly, Víctor Navarro, Tobias Menne, Mi Kwon, Ana África Martín-López, Sridhar Chaganti, Javier Delgado, Claire Roddie, Ariadna Pérez, Jane Norman, Manuel Guerreiro, Adam Gibb, Ana Carolina Caballero, Caroline Besley, Nuria Martínez-Cibrián, Alberto Mussetti, Robin Sanderson, Hugo Luzardo, Sunil Iyengar, Jose Maria Sánchez, Ceri Jones, Juan-Manuel Sancho, Pere Barba, Anne-Louise Latif, Lucia López-Corral, Rafael Hernani, Juan Luis Reguera, Anna Sureda, Alejandro Martin Garcia-Sancho, Mariana Bastos, Pau Abrisqueta, Andrea Kuhnl

Over 60% of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients who receive chimeric antigen receptor (CAR) T cells will experience disease progression. There is no standard next line of therapy and information in this setting is scarce and heterogeneous. We analyzed 387 R/R LBCL patients who progressed after CAR T cells from July 2018 until March 2022 in Spain and the United Kingdom. Median overall survival (OS) was 5.3 months, with significant differences according to the interval between infusion and progression (<2 months [1.9 months], 2–6 months [5.2 months], and >6 months [not reached]). After progression, 237 (61%) patients received treatment. Focusing on the first subsequent therapy, overall (complete) response rates were 67% (38%) for polatuzumab–bendamustine–rituximab (POLA), 51% (36%) for bispecific antibodies (BsAb), 45% (35%) for radiotherapy (RT), 33% (26%) for immune checkpoint inhibitors (ICIs), 25% (0%) for lenalidomide (LENA), and 25% (14%) for chemotherapy (CT). In terms of survival, 12-month progression-free survival and OS was 36.2% and 51.0% for POLA, 32.0% and 50.1% for BsAb, 30.8% and 37.5% for RT, 29.9% and 27.8% for ICI, 7.3% and 20.8% for LENA, and 6.1% and 18.3% for CT. Thirty-two (14%) patients received an allogeneic hematopoietic cell transplant with median OS not reached after a median follow-up of 15.1 months. In conclusion, patients with R/R LBCL who progress within the first 2 months after CAR T-cell therapy have dismal outcomes. Novel targeted agents, such as polatuzumab and BsAbs, can achieve prolonged survival after CAR T-cell therapy failure.

在接受嵌合抗原受体(CAR)T 细胞治疗的复发/难治(R/R)大 B 细胞淋巴瘤(LBCL)患者中,60% 以上的患者会出现疾病进展。目前还没有标准的下一步治疗方案,有关这种情况的信息非常稀少,而且各不相同。我们分析了2018年7月至2022年3月在西班牙和英国接受CAR T细胞治疗后病情进展的387例R/R LBCL患者。中位总生存期(OS)为5.3个月,根据输注与病情进展之间的间隔(<2个月[1.9个月]、2-6个月[5.2个月]和>6个月[未达到])存在显著差异。病情恶化后,237 名(61%)患者接受了治疗。就首次后续治疗而言,波拉珠单抗-本胺嘧啶-利妥昔单抗(POLA)的总体(完全)应答率为67%(38%),双特异性抗体(BsAb)为51%(36%),放疗(RT)为45%(35%),免疫检查点抑制剂(ICIs)为33%(26%),来那度胺(LENA)为25%(0%),化疗(CT)为25%(14%)。在生存率方面,POLA的12个月无进展生存率和OS分别为36.2%和51.0%,BsAb为32.0%和50.1%,RT为30.8%和37.5%,ICI为29.9%和27.8%,LENA为7.3%和20.8%,CT为6.1%和18.3%。32例(14%)患者接受了异基因造血细胞移植,中位随访时间为15.1个月,但未达到中位OS。总之,R/R LBCL 患者在接受 CAR T 细胞治疗后的头 2 个月内病情恶化,预后很差。新型靶向药物,如 polatuzumab 和 BsAbs,可以延长 CAR T 细胞疗法失败后的生存期。
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引用次数: 0
News on sickle cell disease: Heme-driven disordered erythropoiesis 镰状细胞病新闻:血红素驱动的红细胞生成障碍
IF 6.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-05-17 DOI: 10.1002/hem3.75
Francesca Vinchi
<p>Sickle cell disease (SCD) is a hemolytic disorder caused by a point mutation in the β-globin gene leading to the expression of an abnormal hemoglobin (HbS) that has the tendency to polymerize under hypoxic conditions, thus driving red cell sickling. Because of the propensity of sickle red blood cells (RBCs) to break into the circulation and be cleared at a faster rate by reticulo-endothelial macrophages, hemolysis is a hallmark of SCD.<span><sup>1</sup></span> As a consequence, SCD patients present with elevated circulating heme levels and almost complete exhaustion of the hemoglobin and heme scavengers, haptoglobin, and hemopexin.<span><sup>2</sup></span> The saturation of these scavengers leaves heme in a “free” form, loosely bound to other plasma proteins and thus, more prone to accumulate in cells and tissue and promote cell oxidative damage due to its reactive iron moiety.<span><sup>2</sup></span></p><p>Besides hemolysis, disordered erythropoiesis is a feature of hemoglobinopathies, such as β-thalassemia and SCD. Whereas β-thalassemia is hallmarked by ineffective erythropoiesis, less is known about alterations in SCD erythropoiesis, which is likely more effective than in β-thalassemia. A severe misbalance between the expansion of early-stage erythroid progenitor cells and disrupted differentiation of late-stage erythroid precursors drive ineffective erythropoiesis in β-thalassemia.<span><sup>3</sup></span> Although cell death during the Hb synthesis phase of terminal differentiation has been described to contribute to a certain extent to disordered erythropoiesis in SCD,<span><sup>3</sup></span> this mechanism is less pronounced than in β-thalassemia. Erythroid progenitors in SCD have a better ability to terminally differentiate compared to β-thalassemia, and peripheral hemolysis of RBCs due to polymerization of deoxygenated sickle hemoglobin is the major cause of anemia in this disease.</p><p>The mechanisms of disordered erythropoiesis in SCD, and whether and how hemolysis and free heme contribute to them remained in large part unknown to date. Recently, Xiuli An and group investigated sickle erythropoiesis to better dissect potential alterations in the erythroid activity that could further contribute to anemia, besides the hemolytic process.<span><sup>4</sup></span> Taking advantage of a mouse model of SCD, the authors analyzed bone marrow erythropoiesis and compared it to erythropoiesis in a murine model of β-thalassemia. Despite similar induction of erythropoietin (EPO) levels, SCD mice exhibited a modest increase in early progenitors and failed to adequately respond to the hormone compared to β-thalassemia mice, whose erythroblast increase was two-fold higher than in SCD.<span><sup>4</sup></span> This suggests impaired bone marrow erythropoietic activity, which was confirmed by the observation that SCD erythroid progenitor cells showed decreased erythroid colony-forming ability and diminished response to EPO in vitro.<span><sup>4</su
4虽然这项研究发现了血红素通过 IFNα 介导的红细胞中 Cish 的上调抑制 EPO/EPO 受体信号转导,从而在抑制红细胞生成方面发挥了新的作用,但血红素可能会通过产生其他促炎细胞因子(如 IL-6,它对红细胞生成具有已知的抑制作用)而导致 SCD 中红细胞生成受损。重要的是,溶血通过诱导 IFNα 而抑制红细胞生成的观察结果可能对其他溶血性贫血或炎症性贫血有影响,因为循环中的血红素或/和 IFNα 会升高。因此,以 IFNα 途径和/或血红素为靶点可能提供新的治疗方案,不仅能改善 SCD 患者的贫血,还能改善与高血红素和/或 IFNα 水平相关的炎症和感染性疾病的贫血。了解 IFNα 介导的抑制 EPO 反应的分子机制可能有助于开发新的策略,以改善 SCD 以及慢性疾病和炎症性贫血的 EPO 低反应性。这项工作最终强调,除了针对溶血、镰状血红蛋白聚合和血管功能障碍的治疗策略外,针对血红蛋白诱导的炎症反应(包括IFNα信号传导)的替代方法的开发,可通过与其他药物联合改善红细胞生成障碍和贫血,从而为SCD提供治疗益处。Francesca Vinchi撰写了HemaTopic,并起草了由Somersault18:24 BV专业绘制的图表。Vinchi博士是Silence Therapeutics顾问委员会成员,也是RallyBio和Pharmacosmos的顾问。这些关系均与本出版物无关。本研究未获得任何资助。
{"title":"News on sickle cell disease: Heme-driven disordered erythropoiesis","authors":"Francesca Vinchi","doi":"10.1002/hem3.75","DOIUrl":"https://doi.org/10.1002/hem3.75","url":null,"abstract":"&lt;p&gt;Sickle cell disease (SCD) is a hemolytic disorder caused by a point mutation in the β-globin gene leading to the expression of an abnormal hemoglobin (HbS) that has the tendency to polymerize under hypoxic conditions, thus driving red cell sickling. Because of the propensity of sickle red blood cells (RBCs) to break into the circulation and be cleared at a faster rate by reticulo-endothelial macrophages, hemolysis is a hallmark of SCD.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; As a consequence, SCD patients present with elevated circulating heme levels and almost complete exhaustion of the hemoglobin and heme scavengers, haptoglobin, and hemopexin.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The saturation of these scavengers leaves heme in a “free” form, loosely bound to other plasma proteins and thus, more prone to accumulate in cells and tissue and promote cell oxidative damage due to its reactive iron moiety.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Besides hemolysis, disordered erythropoiesis is a feature of hemoglobinopathies, such as β-thalassemia and SCD. Whereas β-thalassemia is hallmarked by ineffective erythropoiesis, less is known about alterations in SCD erythropoiesis, which is likely more effective than in β-thalassemia. A severe misbalance between the expansion of early-stage erythroid progenitor cells and disrupted differentiation of late-stage erythroid precursors drive ineffective erythropoiesis in β-thalassemia.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Although cell death during the Hb synthesis phase of terminal differentiation has been described to contribute to a certain extent to disordered erythropoiesis in SCD,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; this mechanism is less pronounced than in β-thalassemia. Erythroid progenitors in SCD have a better ability to terminally differentiate compared to β-thalassemia, and peripheral hemolysis of RBCs due to polymerization of deoxygenated sickle hemoglobin is the major cause of anemia in this disease.&lt;/p&gt;&lt;p&gt;The mechanisms of disordered erythropoiesis in SCD, and whether and how hemolysis and free heme contribute to them remained in large part unknown to date. Recently, Xiuli An and group investigated sickle erythropoiesis to better dissect potential alterations in the erythroid activity that could further contribute to anemia, besides the hemolytic process.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Taking advantage of a mouse model of SCD, the authors analyzed bone marrow erythropoiesis and compared it to erythropoiesis in a murine model of β-thalassemia. Despite similar induction of erythropoietin (EPO) levels, SCD mice exhibited a modest increase in early progenitors and failed to adequately respond to the hormone compared to β-thalassemia mice, whose erythroblast increase was two-fold higher than in SCD.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; This suggests impaired bone marrow erythropoietic activity, which was confirmed by the observation that SCD erythroid progenitor cells showed decreased erythroid colony-forming ability and diminished response to EPO in vitro.&lt;span&gt;&lt;sup&gt;4&lt;/su","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 5","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.75","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953077","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
Immune-monitoring of myelodysplastic neoplasms: Recommendations from the i4MDS consortium 骨髓增生异常肿瘤的免疫监测:i4MDS 联合会的建议
IF 6.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-05-15 DOI: 10.1002/hem3.64
Cristina A. Tentori, Lin P. Zhao, Benedetta Tinterri, Kathryn E. Strange, Katharina Zoldan, Konstantinos Dimopoulos, Xingmin Feng, Elena Riva, Benjamin Lim, Yannick Simoni, Vidhya Murthy, Madeline J. Hayes, Antonella Poloni, Eric Padron, Bruno A. Cardoso, Michael Cross, Susann Winter, Aida Santaolalla, Bhavisha A. Patel, Emma M. Groarke, Daniel H. Wiseman, Katy Jones, Lauren Jamieson, Charles Manogaran, Naval Daver, Laura Gallur, Wendy Ingram, P. Brent Ferrell, Katja Sockel, Nicolas Dulphy, Nicolas Chapuis, Anne S. Kubasch, Astrid M. Olsnes, Austin Kulasekararaj, Hugues De Lavellade, Wolfgang Kern, Mieke Van Hemelrijck, Dominique Bonnet, Theresia M. Westers, Sylvie Freeman, Uta Oelschlaegel, David Valcarcel, Marco G. Raddi, Kirsten Grønbæk, Michaela Fontenay, Sanam Loghavi, Valeria Santini, Antonio M. Almeida, Jonathan M. Irish, David A. Sallman, Neal S. Young, Arjan A. van de Loosdrecht, Lionel Adès, Matteo G. Della Porta, Catherine Cargo, Uwe Platzbecker, Shahram Kordasti, i4MDS consortium

Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing “immune classes” among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune “risk factors.” By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.

近年来,骨髓增生异常性肿瘤(MDS)的研究取得了重大进展,阐明了与疾病进展密不可分的大量细胞和分子基础。预后模型中的分子内涵大大推进了风险分层,而最近的发现则强调了骨髓环境中免疫失调在 MDS 演变过程中的关键作用。然而,MDS 的免疫疗法并没有取得其他恶性肿瘤的突破性进展,部分原因是缺乏一种免疫分类方法,可以将患者分层,使其接受最佳的靶向免疫疗法。在 MDS 患者中建立 "免疫分级 "的一个关键障碍是缺乏适合临床实验室常规应用的、经过验证的、公认的免疫面板。为此,我们成立了由多学科专家组成的国际 MDS 整合创新免疫学联盟(i4MDS),并为监测 MDS 免疫反应的标准化方法提出了以下建议。i4MDS 的核心目标是开发一种可纳入当前临床风险分层模型的免疫评分。本立场文件首先整合了当前有关 MDS 免疫学的知识。随后,我们与临床和实验室专家合作,介绍了为临床实验室精心设计的流式细胞仪面板和细胞因子检测方法,旨在监测 MDS 患者的免疫状态,评估免疫健康状况并识别潜在的免疫 "风险因素"。通过整合这些免疫学特征数据和分子数据,我们旨在加强患者分层,确定治疗反应性的预测标志物,并加速系统免疫学工具和创新免疫疗法的开发。
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引用次数: 0
Interplay between α-thalassemia and β-hemoglobinopathies: Translating genotype–phenotype relationships into therapies α-地中海贫血和β-血红蛋白病之间的相互作用:将基因型-表型关系转化为疗法
IF 6.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-05-15 DOI: 10.1002/hem3.78
Jim Vadolas, Tiwaporn Nualkaew, Hsiao P. J. Voon, Shahla Vilcassim, George Grigoriadis

α-Thalassemia represents one of the most important genetic modulators of β-hemoglobinopathies. During this last decade, the ongoing interest in characterizing genotype–phenotype relationships has yielded incredible insights into α-globin gene regulation and its impact on β-hemoglobinopathies. In this review, we provide a holistic update on α-globin gene expression stemming from DNA to RNA to protein, as well as epigenetic mechanisms that can impact gene expression and potentially influence phenotypic outcomes. Here, we highlight defined α-globin targeted strategies and rationalize the use of distinct molecular targets based on the restoration of balanced α/β-like globin chain synthesis. Considering the therapies that either increase β-globin synthesis or reactivate γ-globin gene expression, the modulation of α-globin chains as a disease modifier for β-hemoglobinopathies still remains largely uncharted in clinical studies.

α-地中海贫血是β-血红蛋白病最重要的遗传调节因子之一。在过去的十年中,人们对基因型与表型关系的持续关注,使我们对α-球蛋白基因调控及其对β-血红蛋白病的影响有了令人难以置信的认识。在这篇综述中,我们全面介绍了从 DNA 到 RNA 再到蛋白质的 α- 球蛋白基因表达,以及可影响基因表达并潜在影响表型结果的表观遗传机制。在此,我们将重点介绍已确定的α-球蛋白靶向策略,并根据α/β样球蛋白链合成平衡的恢复情况,合理使用不同的分子靶点。考虑到增加β-球蛋白合成或重新激活γ-球蛋白基因表达的疗法,临床研究在很大程度上仍未将调节α-球蛋白链作为β-血红蛋白病的疾病调节剂。
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引用次数: 0
T-cell lymphoblastic lymphoma in constitutional mismatch repair deficiency (CMMRD): Exploring treatment opportunities 体质错配修复缺陷(CMMRD)中的 T 细胞淋巴细胞淋巴瘤:探索治疗机会
IF 6.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-05-12 DOI: 10.1002/hem3.73
Emma Kroeze, Dilys D. Weijers, Michelle M. Kleisman, Uri Ilan, Reno S. Bladergroen, Rico Hagelaar, Jules P. P. Meijerink, Marjolijn C. J. Jongmans, Jan L. C. Loeffen, Roland P. Kuiper
<p>Constitutional mismatch repair deficiency (CMMRD) is a high-risk childhood cancer predisposition syndrome caused by biallelic germline mutations in one of the four mismatch repair (MMR) genes <i>MLH1</i>, <i>MSH2</i>, <i>MSH6</i>, or <i>PMS2</i>. Defective MMR results in the rapid accumulation of mutations and the continuous development of malignancies from an early age. The tumor spectrum of CMMRD patients consists mostly of high-grade brain tumors, gastrointestinal (GI) tumors, and hematologic malignancies.<span><sup>1</sup></span> Hematologic malignancies in CMMRD patients are predominantly lymphomas, most of which are T-cell lymphoblastic lymphomas (T-LBLs).<span><sup>2, 3</sup></span> T-LBL is a malignancy of immature T cells, characterized by infiltration of blasts in the mediastinum and lymph nodes, with fewer than 25% blasts in the bone marrow.<span><sup>4, 5</sup></span> Treatment of T-LBL generally consists of 2-year multiagent chemotherapy (LBL2018, NCT04043494).</p><p>Intensive surveillance protocols for CMMRD patients allow for early detection of brain tumors and GI tumors, providing additional treatment options besides chemotherapy, such as radical surgical resection or radiotherapy.<span><sup>3</sup></span> Moreover, hypermutated brain and GI tumors have shown a good response to PD-1 inhibitors, with hypermutated being defined as >10 mutations/Mb (mut/Mb).<span><sup>6, 7</sup></span> Clinically relevant surveillance strategies for hematologic malignancies are not yet available and it has yet to be studied whether T-LBLs are hypermutated, like brain and GI tumors, and could therefore benefit from checkpoint inhibitors, such as PD-1 inhibitors, as well. Consequently, CMMRD-associated T-LBL is currently treated according to the standard of care treatment strategies for sporadic T-LBL. There are several reasons why standard-of-care treatment strategies might be suboptimal in CMMRD T-LBL patients. Since CMMRD T-LBL patients are often heavily pretreated for previous malignancies, they may have developed chemoresistance. Additionally, previous doses of intensive therapy make patients also more vulnerable to severe complications. Moreover, the current LBL chemotherapeutic backbone consists of a number of mutagenic agents that can cause additional mutations and contribute to the development of new malignancies in these patients.<span><sup>2</sup></span> Additionally, there are indications that MMR deficiency leads to inherent resistance to thiopurines,<span><sup>8-10</sup></span> an important component of T-LBL treatment strategies (LBL2018, NCT04043494). It could therefore be beneficial for CMMRD patients to adapt the LBL backbone by removing the partially toxic and ineffective chemotherapeutic agents and replacing them with other, more effective agents. Molecular characterization of CMMRD-associated T-LBL and sporadic T-LBL could provide insights into molecular similarities and differences between these malignancies, potentially res
这些检查点抑制剂可有效替代诱变剂或硫嘌呤等无效化疗药物。要确定检查点抑制剂是否有效,以及如何将其安全地用于治疗CMMRD相关T-LBL,还需要进一步的研究。此外,我们还研究了一种个性化医疗方法,即通过分析在单个肿瘤中发现的编码突变来寻找高危患者的其他靶点。我们重点研究了SNVs和indels,因为这是CMMRD相关T-LBL基因组异质性最大的地方。分析结果显示,在CMMRD相关T-LBL中,每个肿瘤至少有一个可靶向的事件,此类事件的范围为1-14个。这些事件可以用现有化合物或正在进行的临床试验中研究的化合物作为靶点(佐证资料 S1:表 1)。最常检测到的靶向事件包括NOTCH1、PIK3CD、SMARCA4和BRCA2突变。相比之下,在散发性T-LBL患者中,38名患者中只有5名出现了可被现有化合物或目前正在进行的临床试验靶向的事件。这些数据表明,个体化医疗方法可能对CMMRD相关T-LBL有益,并可能产生替代治疗方案,以补充或部分替代多药化疗。最后,我们探讨了已知驱动散发性T-LBL的畸变在CMMRD相关T-LBL中的频率,以研究发病机制中可能存在的差异。拷贝数畸变(CNAs)的调用采用 GATK v4.0.1.2 最佳实践13。位于断点周围的基因使用 R v3.6.1 中的 GenomicRanges 软件包确定。大于 20 Mb 的 CNA 被包括在内,并使用去噪模型进行视觉验证。9p21 上 CDKN2A/B 基因座的拷贝数缺失也包括在内,这些拷贝数缺失经常小于 20 Mb。与散发性T-LBL相比,CMMRD T-LBL的CNA总数(&gt;20 Mb或9p21缺失)明显较低(p = 0.0012;Wilcoxon秩和检验),这与之前对CMMRD患者脑肿瘤的描述一致14(图1C)。9p21(部分)缺失导致的肿瘤抑制基因座CDKN2A/B缺失是T-LBL中最常检测到的畸变,但在CMMRD相关T-LBL中并不存在(佐证资料S1:图1)。CMMRD T-LBL中CNA数量较少的一个可能解释是,这些肿瘤获得了大量的SNV和嵌合体,因此可能不需要额外的CNA来维持生存和增殖。CMMRD相关T-LBL中也能检测到已知参与散发性T-LBL的大多数其他基因的突变(图1D)。目前的LBL治疗骨干包含多种药物,这些药物可能由于耐药机制而无效,甚至由于突变的引入而有害,这些突变可能导致CMMRD患者发展为第二原发性恶性肿瘤,因此迫切需要对CMMRD相关T-LBL采用替代治疗方案。在比较CMMRD相关T-LBL与散发性T-LBL的分子特征时,我们发现了CMMRD相关T-LBL的各种潜在替代治疗方案,包括使用检查点抑制剂的可能性,以及利用通过个性化医疗方法检测到的可靶向事件。利用其他治疗方案有助于减少这些经常接受大量预处理的患者可能无效且有毒的化疗累积剂量,这可能有助于延长他们的寿命。克莱斯曼(Michelle M. Kleisman)、乌里-伊兰(Uri Ilan)和里科-哈格拉尔(Rico Hagelaar)进行了数据分析,雷诺-布拉德格罗恩(Reno S. Bladergroen)进行了测序,马约利恩-钟曼斯(Marjolijn C. J. Jongmans)提供了数据,朱尔斯-梅耶林克(Jules P. P. Meijerink)获得了资助,扬-洛夫(Jan L. C. Loeffen)和罗兰-库珀(Roland P. Kuiper)指导并设计了这项研究。本研究由 Kinderen Kankervrij 基金 KiKa-393 (EK) 和荷兰癌症协会基金 KWF-12909 (DDW) 赞助。
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