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Primary Breast MALT Lymphoma: Clinical Features and Outcomes From a Single-Institution Experience at Mayo Clinic 原发性乳腺MALT淋巴瘤:来自梅奥诊所单一机构经验的临床特征和结果。
IF 9.9 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-12-29 DOI: 10.1002/ajh.70178
Ahmed Alnughmush, Suheil Albert Atallah-Yunes, Tamer Hellou, Thomas M. Habermann, Yucai Wang, Javier Munoz, Madiha Iqbal, Rebecca L. King, William G. Breen, Jose C. Villasboas, Thomas E. Witzig, Stephen M. Ansell, Grzegorz S. Nowakowski
<p>Extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue (MALT) constitutes approximately 70% of all marginal zone lymphoma (MZL) cases, with the gastric subtype representing the most prevalent anatomical site of origin [<span>1</span>]. Although MALT lymphomas have been described across a broad spectrum of extranodal sites, data specifically addressing primary breast involvement remains limited, largely derived from small case series and population-based analyses, such as those using the SEER database [<span>2-5</span>]. This knowledge gap is particularly relevant in light of epidemiologic trends indicating a decline in the incidence of gastric MALT lymphoma, accompanied by a rising incidence of non-gastric subtypes, including primary breast MALT lymphoma [<span>6, 7</span>].</p><p>Primary breast lymphoma accounts for less than 1% of all non-Hodgkin lymphomas and approximately 3% of extranodal cases. Among these, diffuse large B-cell lymphoma represents the predominant histologic subtype, whereas primary breast MALT lymphoma comprises an estimated 20%–25% of cases [<span>7-9</span>].</p><p>In light of these observations, we sought to provide a comprehensive evaluation of this rare entity, detailing its clinical characteristics, treatment patterns, and outcomes. To our knowledge, this represents the largest single-institution cohort reported to date, with the goal of improving the delineation of clinical features and guiding contemporary management practices.</p><p>Following institutional review board approval, we conducted a retrospective analysis of 38 patients diagnosed with primary breast MALT lymphoma at Mayo Clinic between 1993 and 2024, identified through Epic electronic medical records. Patients were excluded if they had a prior history of MALT lymphoma or if breast involvement occurred as part of disseminated systemic disease. Clinical, pathological, and treatment-related data were abstracted through manual review of the electronic medical records. Statistical analyses were performed using JMP Pro version 17.0.0 (SAS Institute, Cary, NC, USA), with two-sided <i>p</i> values < 0.05 considered statistically significant.</p><p>Event-free survival (EFS) was defined as the interval from diagnosis to disease progression, initiation of subsequent unplanned therapy, or death from any cause and was censored at the date of last follow-up. Overall survival (OS) was defined as the time from diagnosis to death from any cause, with censoring at last known follow-up.</p><p>A total of 38 patients were identified with unilateral or bilateral primary breast MALT lymphoma. The median age at diagnosis was 65.5 years (IQR, 61–74), and the vast majority were female (97.4%). Patient and disease characteristics are summarized in Table 1. Most cases (<i>n</i> = 30, 78.9%) were diagnosed incidentally, with 29 (96.7%) detected on routine screening mammography and one (3.3%) identified via chest CT performed for surveillance of a prior ma
结外粘膜相关淋巴组织(MALT)的结外边缘带淋巴瘤(EMZL)约占所有边缘带淋巴瘤(MZL)病例的70%,其中胃亚型是最常见的解剖学起源部位。尽管MALT淋巴瘤已被广泛地描述为结外部位,但专门针对原发性乳房受损伤的数据仍然有限,主要来自小病例系列和基于人群的分析,例如使用SEER数据库的分析[2-5]。鉴于流行病学趋势表明胃MALT淋巴瘤发病率下降,同时非胃亚型(包括原发性乳腺MALT淋巴瘤)发病率上升,这一知识差距尤为重要[6,7]。原发性乳腺淋巴瘤占所有非霍奇金淋巴瘤的不到1%,约占结外病例的3%。其中,弥漫性大b细胞淋巴瘤是主要的组织学亚型,而原发性乳腺MALT淋巴瘤约占20%-25%[7-9]。根据这些观察结果,我们试图对这种罕见的实体进行全面的评估,详细说明其临床特征、治疗模式和结果。据我们所知,这是迄今为止报道的最大的单机构队列,目的是改善临床特征的描述并指导当代管理实践。经机构审查委员会批准,我们对1993年至2024年间在梅奥诊所诊断为原发性乳腺MALT淋巴瘤的38例患者进行了回顾性分析,这些患者通过Epic电子医疗记录确定。如果患者既往有MALT淋巴瘤病史,或者如果乳房受累是播散性全身性疾病的一部分,则排除。临床、病理和治疗相关的数据是通过人工审查电子病历提取出来的。采用JMP Pro 17.0.0版(SAS Institute, Cary, NC, USA)进行统计学分析,双侧p值&lt; 0.05认为具有统计学意义。无事件生存期(EFS)定义为从诊断到疾病进展、开始后续计划外治疗或因任何原因死亡的时间间隔,并在最后一次随访日期进行审查。总生存期(OS)定义为从诊断到任何原因死亡的时间,并在最后已知随访时进行审查。共有38例患者被确定为单侧或双侧原发性乳腺MALT淋巴瘤。诊断时中位年龄为65.5岁(IQR, 61-74),绝大多数为女性(97.4%)。患者和疾病特征总结于表1。大多数病例(n = 30, 78.9%)是偶然诊断的,其中29例(96.7%)是通过常规筛查乳房x光检查发现的,1例(3.3%)是通过监测既往恶性肿瘤(肉瘤)的胸部CT发现的。在症状表现(n = 6)中,最常见的症状是自检乳房肿块(n = 5),其次是胸痛(n = 1)。诊断时,4例患者(10.5%)为IV期疾病,其中1例并发组织学转化为累及肺部的大b细胞淋巴瘤,3例累及双侧乳房。8例患者(21.1%)有记录的自身免疫性疾病史,包括Sjögren综合征(n = 3)、类风湿性关节炎(n = 1)、系统性红斑狼疮(n = 1)、Addison病合并恶性贫血(n = 1)、颞动脉炎(n = 1)和推定的自身免疫性肾小球肾炎(n = 1)。此外,1例患者(2.6%)既往有乳腺癌胸部放疗史。8例患者(21.1%)有乳腺癌病史:3例既往诊断,5例同时诊断为乳腺MALT淋巴瘤。在同时发生的病例中,有4例是偶然发现的,1例是可触及的肿块。最初的治疗策略包括10例患者(26.3%)单独切除,通常是在切除活检伴有阴性边缘或计划的乳房肿瘤切除术后;单独放疗16例(42.1%),中位放疗剂量为24 Gy (IQR, 8-30 Gy);4例患者(10.5%)接受联合切除和放疗,其中3例患者因并发乳腺癌而接受该方法;利妥昔单抗单药治疗2例(5.3%);1例(2.6%)伴有累及肺部的组织学改变。观察治疗3例(7.9%),其中2例有活动性恶性肿瘤(舌鳞状细胞癌和转移性胆管癌)。2例患者(5.3%)缺少治疗数据。中位随访60.6个月(IQR, 24.6-119.3),估计5年和10年OS率分别为81.6% (95% CI, 62.3%-92.1%)和77% (95% CI, 57.1%-89.5%)。2年和4年的EFS发生率分别为65.8% (95% CI, 49.6%-78.9%)和41% (95% CI, 26.0%-55.6%)(图1)。 在这个小系列中,当按初始治疗方式(放疗与切除)分层时,在EFS或OS中均未观察到统计学上的显著差异(图S1)。12例患者复发,中位复发时间为35.4个月(IQR, 19.3-54.8)。在单独切除的患者中(n = 10), 5例(50%)复发,涉及同侧乳房(n = 1),对侧乳房(n = 2)和远处部位(n = 2)。在单独接受放射治疗的患者中(n = 16), 7例(43.8%)复发,包括同侧乳房(n = 2),对侧乳房(n = 2)和远处或局部部位(n = 3)的复发。在远处或局部复发的5例患者中,部位包括左眼眶(n = 2)、右腮腺(n = 1)、骨髓和脾脏(n = 1)和右胸壁(n = 1);后者是乳腺外唯一的局部复发病例。2例同侧乳房放疗后复发患者,1例诊断时双侧病变,接受双侧放疗(30 Gy),另1例最初接受低剂量放疗(4 Gy)。此外,3例患者在其他粘膜部位复发:左眼眶(n = 2)和右腮腺(n = 1);其中,只有1人有自身免疫性疾病史(Sjögren综合征)(图S2)。组织学转化为弥漫性大b细胞淋巴瘤2例(5.3%);1例在初次诊断时出现,而2例发生在19年后。观察期内死亡的9例患者中,死亡原因包括胃肠出血(n = 1)、头颈部转移性鳞状细胞癌(n = 1)、失代偿性心力衰竭(n = 1)、脑出血(n = 1)、败血症(n = 1)。4例患者死亡原因不明;值得注意的是,这些人在死亡前都没有疾病复发或进展的记录证据。我们的报告提供了一个详细的评估临床特征和预后的患者原发性乳腺MALT淋巴瘤。诊断时的中位年龄和明显的女性优势与先前的系列一致[2,4,7]。虽然这种性别分布可以部分解释为常规乳腺癌筛查,但它也可能受到乳腺组织体积解剖差异的影响。虽然先前已提出激素的影响,但没有明确的关联或因果关系[3,10]。8例乳腺癌患者中有5例同时诊断为乳腺MALT淋巴瘤。虽然该亚组的生存率较低,但差异没有统计学意义,更可能归因于潜在的乳腺癌而不是淋巴瘤相关因素。观察到的有利生存结果与MZL的惰性性质相一致,MZL的死亡率通常可归因于非淋巴瘤相关原因[11]。这些发现与先前的机构系列和基于人群的乳腺MALT淋巴瘤分析一致[3,5,7]。在国际结外淋巴瘤研究组(n = 24)的有限系列研究中,5年和10年的OS率分别为92%和64%。大约三分之一的患者经历疾病复发,最常见的是累及同侧或对侧乳房,而不是远处部位。虽然MALT淋巴瘤的遗传图谱因解剖部位而异,但许多与慢性抗原刺激有关,通常在持续感染或自身免疫性bbb的背景下产生。值得注意的是,我们的队列中有3例患者在与MALT淋巴瘤典型相关的粘膜部位复发——2例在眼眶,1例在腮腺——这增加了不同部位淋巴瘤发生重叠机制的可能性。Ivanova等人的基因组分析表明,乳腺MALT淋巴瘤主要是突变驱动的,在他们的15例病例中没有发现MALT1易位。有趣的是,突变谱显示与眼眶MALT淋巴瘤相似,支持这些结外部位[13]之间存在共同的生物学特征。虽然受样本量的限制,我们的研究结果支持使用标准剂量放射治疗或手术切除作为局部疾病控制的有效方式。在我们的研究中,单纯的切除与较差的生存结果无关。在姑息性环境之外使用低剂量辐射(4gy)仍然存在争议,因为历史
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引用次数: 0
Correction to “Budesonide, Added to PTCy ‐Based Regimen, for Prevention of Acute GI GVHD After Allogeneic Stem Cell Transplantation” 更正“布地奈德加入PTCy - Based方案,预防同种异体干细胞移植后急性GI GVHD”
IF 12.8 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-12-27 DOI: 10.1002/ajh.70179
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引用次数: 0
Can We Really Believe This Platelet Count? 我们真的能相信血小板计数吗?
IF 9.9 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-12-27 DOI: 10.1002/ajh.70172
James Manning, Simona Deplano, Ketan Patel, Barbara J. Bain

A 64-year-old woman presented to the hematology clinic for follow up of refractory chronic cold agglutinin disease with hepatic iron overload secondary to a chronic red cell transfusion burden. Management had included single-agent rituximab and ciclosporin, to which the disease had proven refractory. She had recently received a first cycle of bendamustine and rituximab. On review preceding a second cycle, she was tired and lightheaded and scleral icterus was noted. A blood sample was taken urgently and conveyed to the laboratory for testing. Full blood count results, compared to results from three weeks earlier, are tabulated.

Given the unexpected abnormalities in the blood count, an urgent blood film was made. This showed only small red cell agglutinates (left image, ×100 objective) and did not confirm the apparent thrombocytosis. The most striking feature was the presence of numerous red cell fragments, many of which were spherical and some of which were budding from red cells (both images). There were small numbers of more angular fragments. The thrombocytosis was factitious and attributable to schistocytes being counted as platelets. The leucocytosis was also factitious and attributable to loose clumps of platelets and debris being counted as leucocytes. All neutrophils were cytologically abnormal with blurred nuclear and cytoplasmic outlines and increased granularity (right image). The findings were not suggestive of a microangiopathic hemolytic anemia since the schistocytes were not often angular but rather were often microspherocytes and could be seen budding from red cells. These findings suggest the effect of heat. These distinctive heat effects can be seen both in patients suffering from burns and also when a blood sample has been inappropriately heated in vitro. Further investigation revealed that the phlebotomist had transported the patient's blood specimen to the laboratory in a mug of hot water.

Erroneous results of a blood count can result from preanalytical, analytical, or post-analytical errors. This is an example of an uncommon preanalytical error. It is important that when it is necessary to keep a blood specimen warm it is kept at a controlled temperature of 37°C. Staff training is also important.

The authors declare no conflicts of interest.

一名64岁女性,因难治性慢性感冒凝集素病并发肝铁超载继发于慢性红细胞输血负担,到血液科诊所接受随访。治疗包括单药利妥昔单抗和环孢素,疾病已被证明难治性。她最近接受了第一个周期的苯达莫司汀和利妥昔单抗。在第二次周期前复查时,她感到疲倦和头晕,并注意到巩膜黄疸。紧急采集了血液样本并送到实验室进行检测。将全血细胞计数结果与三周前的结果进行比较,制成表格。考虑到血液计数的意外异常,紧急制作了血液片。这只显示了小的红细胞凝集(左图,×100客观),并没有证实明显的血小板增多。最显著的特征是存在大量的红细胞碎片,其中许多是球形的,其中一些是从红细胞中萌芽的(两幅图)。还有少量棱角分明的碎片。血小板增多是人为的,可归因于血吸虫细胞被算作血小板。白细胞增多也是人为的,可归因于松散的血小板团块和碎片被计数为白细胞。所有中性粒细胞细胞学异常,细胞核和细胞质轮廓模糊,粒度增加(右图)。该结果不提示微血管病性溶血性贫血,因为裂细胞不常呈角状,而常为微球细胞,可从红细胞中看到出芽。这些发现表明了热量的影响。这些独特的热效应既可以在遭受烧伤的病人身上看到,也可以在体外不适当地加热血液样本时看到。进一步调查显示,该名抽血师曾将病人的血液样本装在一大杯热水中运送至化验所。血液计数的错误结果可能是由于分析前、分析后或分析后的错误造成的。这是一个不常见的分析前错误的例子。重要的是,当需要保持血液标本温暖时,将其保持在37°C的控制温度下。员工培训也很重要。作者声明无利益冲突。
{"title":"Can We Really Believe This Platelet Count?","authors":"James Manning,&nbsp;Simona Deplano,&nbsp;Ketan Patel,&nbsp;Barbara J. Bain","doi":"10.1002/ajh.70172","DOIUrl":"10.1002/ajh.70172","url":null,"abstract":"<p>\u0000 \u0000 </p><p>A 64-year-old woman presented to the hematology clinic for follow up of refractory chronic cold agglutinin disease with hepatic iron overload secondary to a chronic red cell transfusion burden. Management had included single-agent rituximab and ciclosporin, to which the disease had proven refractory. She had recently received a first cycle of bendamustine and rituximab. On review preceding a second cycle, she was tired and lightheaded and scleral icterus was noted. A blood sample was taken urgently and conveyed to the laboratory for testing. Full blood count results, compared to results from three weeks earlier, are tabulated.\u0000 </p><p>Given the unexpected abnormalities in the blood count, an urgent blood film was made. This showed only small red cell agglutinates (left image, ×100 objective) and did not confirm the apparent thrombocytosis. The most striking feature was the presence of numerous red cell fragments, many of which were spherical and some of which were budding from red cells (both images). There were small numbers of more angular fragments. The thrombocytosis was factitious and attributable to schistocytes being counted as platelets. The leucocytosis was also factitious and attributable to loose clumps of platelets and debris being counted as leucocytes. All neutrophils were cytologically abnormal with blurred nuclear and cytoplasmic outlines and increased granularity (right image). The findings were not suggestive of a microangiopathic hemolytic anemia since the schistocytes were not often angular but rather were often microspherocytes and could be seen budding from red cells. These findings suggest the effect of heat. These distinctive heat effects can be seen both in patients suffering from burns and also when a blood sample has been inappropriately heated in vitro. Further investigation revealed that the phlebotomist had transported the patient's blood specimen to the laboratory in a mug of hot water.</p><p>Erroneous results of a blood count can result from preanalytical, analytical, or post-analytical errors. This is an example of an uncommon preanalytical error. It is important that when it is necessary to keep a blood specimen warm it is kept at a controlled temperature of 37°C. Staff training is also important.</p><p>The authors declare no conflicts of interest.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"566-567"},"PeriodicalIF":9.9,"publicationDate":"2025-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70172","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Economic Burden of Sickle Cell Disease: A Retrospective Study of Pediatric and Adult Individuals With Medicaid Coverage From 2016 to 2020 镰状细胞病的经济负担:2016年至2020年医疗补助覆盖的儿童和成人的回顾性研究
IF 9.9 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-12-24 DOI: 10.1002/ajh.70146
Giovanna Tedesco Barcelos, Telma Peixoto, Jose Alvir, Jay Lin, Christine L. Baker

There is limited information regarding the contemporary real-world clinical and financial burden of Medicaid enrollees with sickle cell disease (SCD) in the United States. Using the IBM MarketScan Medicaid database (7/2016–12/2020), individuals with ≥ 3 SCD diagnoses were matched 1:1 on age, gender, and race to individuals without SCD. Continuous coverage was required during 6-month baseline and 12-month follow-up periods. Follow-up healthcare resource utilization (HCRU) and costs were compared between the SCD and non-SCD cohorts in separate analyses of the pediatric (< 18 years, n = 4723 per cohort, 52% male, mean age: 8.8 years) and adult (≥ 18 years, n = 5597 per cohort, 60% female, mean age: 35.1 years) populations. During follow-up, pediatric individuals with SCD had significantly more hospitalizations (0.8 vs. 0.03) with longer length of stay (LOS, 3.0 vs. 0.1 days), outpatient visits (19.5 vs. 10.8), prescriptions (12.8 vs. 3.8), and higher mean total costs ($18 900 vs. $2127) than individuals without SCD; hospitalizations (39.6-fold) and pharmacy use (11.9-fold) accounted for the largest cost differences. Adults with SCD had significantly more hospitalizations (2.1 vs. 0.1; LOS: 11.3 vs. 0.7 days), outpatient visits (46.5 vs. 22.5), office visits (7.7 vs. 4.9), prescriptions (29.5 vs. 13.7), and higher mean total costs ($45 114 vs. $6039) than adults without SCD; hospitalizations (18.7-fold) and ER visits (12.7-fold) had the greatest cost differences. In conclusion, pediatric and adult Medicaid enrollees with SCD had significantly higher HCRU and costs, demonstrating an unmet need for improved management of SCD to potentially reduce the economic burden for both payers and individuals with SCD.

关于美国镰状细胞病(SCD)医疗补助入选者的临床和经济负担的信息有限。使用IBM MarketScan Medicaid数据库(2016年7月- 2020年12月),有≥3次SCD诊断的个体与没有SCD的个体在年龄、性别和种族上进行1:1匹配。在6个月的基线期和12个月的随访期需要连续覆盖。在单独的儿科(18岁,每队列n = 4723人,52%男性,平均年龄8.8岁)和成人(≥18岁,每队列n = 5597人,60%女性,平均年龄35.1岁)人群分析中,比较SCD和非SCD队列的随访医疗资源利用率(HCRU)和成本。随访期间,SCD患儿的住院次数(0.8比0.03)、住院时间(LOS, 3.0比0.1天)、门诊次数(19.5比10.8)、处方(12.8比3.8)和平均总费用(18900美元比2127美元)显著高于无SCD患者;住院治疗(39.6倍)和药房使用(11.9倍)是最大的成本差异。与没有SCD的成年人相比,SCD成人的住院次数(2.1 vs. 0.1; LOS: 11.3 vs. 0.7天)、门诊次数(46.5 vs. 22.5)、办公室就诊次数(7.7 vs. 4.9)、处方(29.5 vs. 13.7)和更高的平均总费用(45114美元vs. 6039美元)显著增加;住院(18.7倍)和急诊(12.7倍)的费用差异最大。总之,患有SCD的儿童和成人医疗补助入选者的HCRU和费用明显较高,表明需要改进SCD管理,以潜在地减轻支付者和SCD患者的经济负担。
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引用次数: 0
Beyond the Usual Suspects: RSV Infection in Patients With Hematological Malignancies Compared to Influenza and SARS-COV-2—A Report From the EPICOVIDEHA/EPIRESEHA Registry 超越通常的怀疑:与流感和SARS - COV - 2相比,血液系统恶性肿瘤患者的RSV感染-来自EPICOVIDEHA/EPIRESEHA登记处的报告
IF 9.9 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-12-24 DOI: 10.1002/ajh.70166
Jon Salmanton-García, Francesco Marchesi, Milan Navrátil, Iker Falces-Romero, Maria Ilaria Del Principe, Jorge Labrador, Klára Piukovics, Verena Petzer, Monika M. Biernat, Michail Samarkos, Dario Leotta, Nicola Fracchiolla, Anna Dąbrowska-Iwanicka, Antonio Vena, Benjamín Víšek, Yavuz M. Bilgin, Jens Van Praet, Mario Virgilio Papa, Inmaculada Heras Fernando, Francesca Farina, Ľuboš Drgoňa, Josip Batinić, Barbora Weinbergerová, Nurettin Erben, Joanna Drozd-Sokołowska, Patricia García-Ramírez, Annarosa Cuccaro, Martin Čerňan, Nicola Sgherza, Tobias Lahmer, Donald C. Vinh, Gaëtan Plantefeve, Alberto López-García, Chiara Cattaneo, Nikola Pantić, Sofya Khostelidi, Julio Dávila-Valls, Andrés Soto-Silva, László Imre Pinczés, Ferenc Magyari, Reham Abdelaziz Khedr, Michelina Dargenio, Martijn Bakker, Igor Stoma, Carolina Garcia-Vidal, Ildefonso Espigado, Claudio Cerchione, Caterina Buquicchio, Zlate Stojanoski, Gabriele Magliano, Stefanie K. Gräfe, Avinash Aujayeb, Lucia Prezioso, Vladimir Otašević, Maria Merelli, Erica Mackenzie, Andreas Glenthøj, Eleni Gavriilaki, Noha Eisa, Mario Delia, Alessandro Busca, Ahlam Almasari, Tatjana Adžić-Vukičević, Ivana Urošević, Uluhan Sili, Carolina Miranda-Castillo, Gustavo-Adolfo Méndez, Stef Meers, Monia Marchetti, Nicola Coppola, Gökçe Melis Çolak, Darko Antić, Ditte Stampe Hersby, Pellegrino Musto, Milche Cvetanoski, Martin Schönlein, Tommaso Francesco Aiello, Elena Arellano, Davide Nappi, Sonia Martín-Pérez, Mirjana Mitrović, Raul Cordoba, Romane Prin, Marta Callejas-Charavia, Gina Varricchio, Martina Bavastro, Alessandro Limongelli, Amalia N. Anastasopoulou, Alessandra Romano, Dominik Wolf, Kevin Nguyen, Lukas Van Den Ven, Alessia Di Pilla, Antonio Giordano, Oliver A. Cornely, Livio Pagano

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引用次数: 0
Acute Exercise Challenge and Airway Dynamics in Youth With Sickle Cell Anemia: A Multicenter Study 青少年镰状细胞性贫血的急性运动挑战和气道动力学:一项多中心研究
IF 9.9 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-12-20 DOI: 10.1002/ajh.70170
Robyn T. Cohen, Jane S. Hankins, Kirsten K. Ness, Lewis L. Hsu, Tracy Baynard, Amy Tang, Shlomit Radom-Aizik, Kevin Guerrero, Mark Rodeghier, Robert I. Liem

Sickle cell anemia (SCA) leads to reduced physical functioning and cardiopulmonary fitness. Prior studies suggest that airway hyperresponsiveness to bronchoprovocation testing is common in SCA, but the prevalence of exercise-induced bronchospasm (EIB) is understudied. We hypothesized that EIB is more common in children with SCA than in controls. Non-asthmatic subjects 10–21 years old with SCA and race-matched controls underwent (1) maximal Cardiopulmonary Exercise Testing (CPET) by cycle ergometry and (2) a Controlled Intensity Interval Test (CIIT) consisting of eight bouts of constant workload cycling, randomized to 50% (moderate) or 70% (vigorous) of peak workload. Spirometry was performed pre/post CPET and CIIT. Multivariable logistic regression models tested associations between SCA status and EIB in response to CPET and CIIT. Compared to controls, subjects with SCA demonstrated lower hemoglobin, reduced baseline spirometry values, and decreased CPET maximal workload. Baseline lower airway obstruction and completion rates for CPET and CIIT were similar between groups. No adverse events occurred. The percentage of participants who met criteria for EIB did not differ between subjects and controls after CPET (21% vs. 26%, p = 0.537) or CIIT (32% vs. 17%, p = 0.126). In adjusted models, SCA status was not associated with EIB after CPET or CIIT. EIB was not more common in subjects with SCA versus controls after maximal CPET or submaximal exercise challenge of longer duration. Further research is needed to inform the development of exercise guidelines and to better understand the effects of exercise on airway dynamics in SCA.

Trial Registration: ClinicalTrials.gov identifier: NCT03653676.

镰状细胞性贫血(SCA)会导致身体机能和心肺功能下降。先前的研究表明,气道对支气管刺激试验的高反应性在SCA中很常见,但运动诱发支气管痉挛(EIB)的患病率尚未得到充分研究。我们假设EIB在SCA患儿中比对照组更常见。10-21岁患有SCA的非哮喘受试者和种族匹配的对照组接受了(1)最大心肺运动测试(CPET)和(2)控制强度间歇测试(CIIT),包括8组恒定负荷循环,随机分配到峰值负荷的50%(中等)或70%(剧烈)。在CPET和CIIT前后进行肺活量测定。多变量逻辑回归模型检验了SCA状态与EIB对CPET和CIIT的反应之间的关联。与对照组相比,SCA受试者表现出较低的血红蛋白,降低的基线肺活量测定值和降低的CPET最大工作量。两组间CPET和CIIT的基线低气道阻塞率和完成率相似。无不良事件发生。在CPET(21%对26%,p = 0.537)或CIIT(32%对17%,p = 0.126)后,符合EIB标准的参与者百分比在受试者和对照组之间没有差异。在调整后的模型中,CPET或CIIT后SCA状态与EIB无关。在长时间的最大CPET或次最大运动挑战后,SCA受试者的EIB并不比对照组更常见。需要进一步的研究来为运动指南的制定提供信息,并更好地了解运动对SCA患者气道动力学的影响。试验注册:ClinicalTrials.gov标识符:NCT03653676。
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引用次数: 0
A Combination of Plerixafor and Filgrasting Promotes Successful CD34+ Cell Collection for CRISPR/Cas9 Therapy in Sickle Cell Disease Patients With Insufficient Response to Plerixafor Alone Plerixafor和Filgrasting联合应用可成功收集CD34+细胞,用于单药Plerixafor反应不足的镰状细胞病患者的CRISPR/Cas9治疗。
IF 9.9 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-12-19 DOI: 10.1002/ajh.70167
Francesco Arcioni, Marta Bonetti, Antonella Sau, Marco Zecca, Mohsen Alzahrani, Bader Alahmari, Husam Alsadi, Ayman Almozaini, Mazen Ahmed, Mohammed Essa, Cesare Perotti, Claudia Del Fante, Cecilia Passeri, Ornella Iuliani, Anna C. Russo, Mauro Di Ianni, Mauro Marchesi, Barbara Luciani Pasqua, Marina Onorato, Laura Berchicci, Antonio Pierini, Tiziana Zei, Roberta Iacucci, Carla Cerri, Grazia Gurdo, Alessandra Innocente, Ilaria Capolsini, Paolo Gorello, Raffaella Colombatti, Raffaella Origa, Maurizio Caniglia
<p>Sickle cell disease (SCD) is an inherited hemoglobinopathy caused by a point mutation in the β-globin gene, with production of sickle hemoglobin (HbS) [<span>1, 2</span>], chronic hemolytic anemia, recurrent vaso-occlusive crises (VOCs), and progressive end-organ damage [<span>1</span>]. Although hydroxyurea and chronic transfusion therapy have improved clinical outcomes, these therapies are not curative [<span>3</span>]. Hematopoietic stem cell transplantation (HSCT) represents the only established curative approach, but its application is limited by donor availability [<span>3</span>].</p><p>Recently, gene-editing strategies, including CRISPR/Cas9 or conventional gene addition therapies, have been developed. CRISPR/Cas9 technology to disrupt the BCL11A erythroid enhancer and increase fetal hemoglobin (HbF) expression has emerged as a promising treatment [<span>4</span>]. This therapeutic approach has been validated in pivotal Phase 3 trials of exagamglogene autotemcel (exa-cel), which demonstrated near complete elimination of vaso-occlusive crises in patients with SCD and transfusion independence in most of those with β-thalassemia [<span>4, 5</span>].</p><p>However, these protocols require the collection of large numbers of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs), with a minimum target of 20 × 10<sup>6</sup> CD34+ cells/kg to enable successful ex vivo manipulation and engraftment [<span>6, 7</span>]. Standard granulocyte-colony stimulating factor (G-CSF)-based mobilization is generally contraindicated due to the risk of triggering VOCs, ACS, multi-organ failure, and even death, particularly in the presence of high HbS levels [<span>8, 9</span>].</p><p>We report a case series of five patients with SCD who underwent multiple mobilization attempts in preparation for CRISPR/Cas9-based gene-editing therapy. 4/5 patients were being treated with hydroxyurea, discontinued 8 weeks before the mobilization, without reintroduction between cycles. All patients received intensive red blood cell exchange transfusion to reduce HbS to < 20% and prophylactic anticoagulation or antiplatelet therapy. Initial collection with plerixafor alone failed to achieve the CD34+ cell target in all patients. The addition of filgrastim resulted in a marked increase in CD34+ yield, without triggering VOCs or other complications. In patients who fail mobilization and manufacturing with single-agent plerixafor, no alternative mobilization strategies are available other than the combination of G-CSF and plerixafor.</p><p>Before mobilization, all patients were informed about the use of G-CSF and the associated risks (VOCs, ACS, multi-organ failure, and even death, particularly in the presence of high HbS levels). They provided both oral and written informed consent.</p><p>A 29-year-old male with compound heterozygous SCD (HbS/β<sup>+</sup> genotype) was treated at the Pediatric Oncohematology Department in Pescara and considered for CRISPR/Cas9-based
镰状细胞病(SCD)是一种由β-珠蛋白基因点突变引起的遗传性血红蛋白病,伴有镰状血红蛋白(HbS)的产生[1,2]、慢性溶血性贫血、复发性血管闭塞危像(VOCs)和进行性终末器官损伤[1]。虽然羟基脲和慢性输血疗法改善了临床结果,但这些疗法并不能完全治愈。造血干细胞移植(HSCT)是唯一确定的治疗方法,但其应用受到供体可用性的限制。最近,包括CRISPR/Cas9或传统基因添加疗法在内的基因编辑策略已经开发出来。CRISPR/Cas9技术破坏BCL11A红系增强子并增加胎儿血红蛋白(HbF)表达已成为一种有前景的治疗方法。这种治疗方法已经在exa-cel的关键3期试验中得到验证,该试验表明SCD患者几乎完全消除了血管闭塞危象,并且大多数β-地中海贫血患者无需输血[4,5]。然而,这些方案需要收集大量自体CD34+造血干细胞和祖细胞(HSPCs),最低目标为20 × 106 CD34+细胞/kg,才能成功地进行体外操作和移植[6,7]。基于粒细胞集落刺激因子(G-CSF)的标准动员通常是禁忌的,因为它有触发VOCs、ACS、多器官衰竭甚至死亡的风险,特别是在HbS水平高的情况下[8,9]。我们报告了5例SCD患者的病例系列,他们经历了多次动员尝试,为基于CRISPR/ cas9的基因编辑治疗做准备。4/5患者接受羟基脲治疗,在活动前8周停药,两个周期之间没有重新引入羟基脲。所有患者均接受强化红细胞交换输注,将HbS降至20%,并进行预防性抗凝或抗血小板治疗。在所有患者中,单独使用plerixafor的初始收集未能达到CD34+细胞靶标。非格司汀的加入导致CD34+产率显著增加,而没有引发VOCs或其他并发症。对于使用单药plerixafor不能进行动员和生产的患者,除了G-CSF和plerixafor联合使用外,没有其他的动员策略可用。在动员之前,所有患者都被告知G-CSF的使用和相关的风险(VOCs、ACS、多器官衰竭,甚至死亡,特别是在高HbS水平的情况下)。他们提供了口头和书面的知情同意。一名患有复合杂合子SCD (HbS/β+基因型)的29岁男性在佩斯卡拉儿科肿瘤血液科接受治疗,并考虑进行基于CRISPR/ cas9的基因编辑治疗(表1)。最初的动员尝试包括哌利沙单药治疗,之前进行两次EEX治疗,将HbS降低到12.6%。抗血栓预防包括每天服用依诺肝素4000 IU。连续3天进行白细胞分离,收集16.2 × 106个CD34+细胞/kg(表2)。第二周期采用哌利沙与非格拉西汀联合治疗,HbS为11.7%。血栓预防给予依诺肝素。两期均未发生挥发性有机化合物或其他急性并发症。非格昔汀给药后2天的单采产生30.2 × 106个CD34+细胞,增加1.9倍,相当于86.4%(表2)。一名23岁男性纯合子SCD (HbSS基因型)患者在意大利佩鲁贾医院儿科血液肿瘤科接受治疗,作为采用CRISPR/Cas9技术的基因编辑方案的一部分,接受了自体造血干细胞动员(表1)。第一个动员周期单独使用百利沙(HbS为16.89%)。抗血栓预防给予依诺肝素。连续进行3次单采,累积产量为7.9 × 106个CD34+细胞/kg(表2)。第二次活动尝试使用非格司汀和普利沙福的组合。白细胞生成素。HbS为8.34%。用依诺肝素维持抗血栓预防。总CD34+细胞产量为73.3 × 106细胞/kg,比第一次动员增加827%。在两个动员周期内均未报告VOCs或其他不良反应(表2)。第三例患者为一名21岁男性,患有纯合子SCD (HbSS基因型),在沙特阿拉伯利雅得成人血液科接受治疗(表1)。第一个动员周期连续3天单独使用百利沙,HbS为7.5%。CD34+总产量为14.34 × 106个CD34+细胞/kg。第二次动员尝试使用相同剂量的plerixafor, HbS为6.9%。进行两次单采,累积产量为9.31 × 106个CD34+细胞/kg。 两次动员周期的CD34+细胞总数为23.65 × 106/kg,但未能达到制造目标(表2)。然后开始第三次动员尝试,使用非格司汀和普利沙福的组合。给予依诺肝素抗凝治疗。33.1 × 106个CD34+细胞/kg的累积产量超过了最低阈值,并允许进行进一步的基因编辑程序。使用G-CSF无不良事件报告(表2)。一名患有SCD (HbSS基因型)的32岁女性患者在沙特利雅得成人血液科接受了四个周期的自体造血干细胞动员治疗(表1)。第一个动员周期涉及单独的plerixafor (HbS至9.4%),累积CD34+细胞产量为19.31 × 106。第二次动员尝试,同样不含G-CSF,再次使用plerixafor进行3天(HbS 4.7%),累积产量为6 × 106个CD34+细胞/kg。第三个动员周期(HbS 5.2%)仅使用plerixafor, CD34的收集量为6.59 × 106细胞/kg(表2)。从三个动员周期收集的总剂量未能达到可接受的生产收率。因此,计划了第四个动员周期。在第四个周期中,患者接受非格昔汀和普利沙福(HbS 6.4%)。两次单采分别产生30.8 × 106个CD34+细胞/kg,达到基因编辑程序的目标阈值。无不良事件报告(表2)。一名患有复合杂合子SCD (HbS/β+基因型)的21岁女性在意大利帕维亚的San Matteo医院接受治疗,并登记接受CRISPR/ cas9介导的基因编辑治疗(表1)。HbS为18%,抗血栓预防包括依诺肝素。连续三次只用plerixafor的白细胞分离总共产生5.76 × 106个细胞/kg。无VOCs及其他急性并发症发生(表2)。在第二个动员和收集周期采用联合方案。HbS为8%,在动员治疗开始前5天开始使用抗血小板乙酰水杨酸;非格拉西汀与普利沙福联合用药。连续两次单采累积产量为31.73 × 106细胞/kg,增加4.5倍(+451%)。在G-CSF暴露或收集期间,未观察到voc、白细胞停滞或其他不良事件(表2)。所有5名患者均通过输注编辑过的细胞产品完成了整个疗程,迄今为止未出现任何与动员期使用非格司汀相关的并发症。在单独使用plerixafor的CLIMB scd -121中,动员周期的中位数为2个(范围1-6),32%的患者进行了3个或更多的周期,另外3名患者由于细胞收集不足而停止使用。我们的病例系列建立在这些发现的基础上,表明在5例初始plerixafor动员失败的SCD患者中,在随后的周期中添加非格司汀能够成功收集≥20 × 106个CD34+细胞/kg,满足CRISPR编辑的阈值,在动员或分离期间没有voc或急性并发症。这些发现提供了越来越多的证据,表明G-CSF在对照临床环境中谨慎使用时,可以安全地纳入SCD患者的动员方案。从历史上看,G-CSF在这一人群中是禁忌症,但最近的研究表明,适当的预防措施,如红细胞穿刺将HbS水平降低到20%以下,充足的水合作用和密切的临床监测,可以减轻这些风险,并允许安全有效的干细胞收集。我们的经验与现有的SCD动员方案一致:所有患者都进行了强化的双周EEX,以将HbS降至20%以下(所有患者的动员前EEX持续时间为数月),接受充分的水化治疗,并给予预防性抗凝和/或抗血小板治疗,这些共同
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引用次数: 0
Basiliximab in the Prophylaxis of aGVHD for Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients With Thalassemia Major: A Prospective, Multicenter, Open-Label, Randomized Controlled Study Basiliximab在地中海贫血患者非亲属供体造血干细胞移植中预防aGVHD:一项前瞻性、多中心、开放标签、随机对照研究
IF 9.9 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-12-19 DOI: 10.1002/ajh.70169
Zhenbin Wei, Rongrong Liu, Lingling Shi, Qiaochuan Li, Lianjin Liu, Baoshi Zheng, Chunjie Qin, Hong Chen, Guyun Wang, Meiqing Wu, Gaohui Yang, Ruolin Li, Zhaoping Gan, Qi Zhou, Jing Fan, Xuemei Zhou, Yinghua Chen, Zhiyu Zeng, Zhongming Zhang, Yongrong Lai
<p>We present the first prospective, multicenter, randomized controlled trial (RCT) evaluating Basiliximab prophylaxis for acute graft-versus-host disease (GVHD) in thalassemia major (TM) patients undergoing Matched unrelated donor hematopoietic stem-cell transplantation (MUD-HSCT). This study was registered at ClinicalTrials.gov [#NCT02342145]. This study addresses a critical unmet need in optimizing GVHD prevention strategies in this high-risk population.</p><p>Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains the only curative therapy currently available for thalassemia major (TM). While HLA-matched sibling-donor (MSD) transplantation yields > 90% overall survival (OS) and > 80% thalassemia-free survival (TFS), only 25%–30% of patients have available MSD [<span>1, 2</span>]. Matched unrelated donor (MUD) transplantation thus represents a common alternative, but graft-versus-host disease, graft rejection and transplant-related mortality (TRM) remain obstacles.</p><p>Basiliximab, an IL-2 receptor (CD25) antagonist, has demonstrated efficacy in solid organ transplant rejection prophylaxis and in steroid-refractory aGVHD. Our trial rigorously compares standard GVHD prophylaxis with or without Basiliximab to clarify its prophylactic role in unrelated donor HSCT.</p><p>Three Chinese transplant centers enrolled patients (April 2015–September 2021) with transfusion-dependent TM, adequate organ function and no active infection or hepatitis. Key exclusions were HIV positivity, cytomegalovirus (CMV) or Epstein–Barr virus (EBV) viremia > 200 copies/ml, or transaminases > 4 × ULN. Written parental consent was obtained.</p><p>After eligibility confirmation, patients were sequentially numbered per center; alternate numbers were assigned to Basiliximab or control arms (open-label). All received identical myelo-ablative conditioning: fludarabine 50 mg/m<sup>2</sup> days −12 to −10, busulfan 1 mg/kg q6 h days −9 to −6, cyclophosphamide 50 mg/kg days −5 to −2 and anti-thymocyte (ATG, Thymoglobulin) 2.5 mg/kg days −4 to −1. Hydroxyurea 30 mg/kg had been given for 2 months pre-conditioning. Peripheral-blood stem cells were infused from 10/10 or 9/10 HLA matching MUDs. GVHD prophylaxis in both arms consisted of tacrolimus (FK506 0.03 mg/kg/day, target 5–15 ng/mL) from day −3, methotrexate (15 mg/m<sup>2</sup> day +1, 10 mg/m<sup>2</sup> days +3, +6, +11) and mycophenolate mofetil (MMF 250 mg/day) for 90 days. Basiliximab-arm patients additionally received 10 mg (< 35 kg) or 20 mg (≥ 35 kg) intravenously on days 0 and +4. Follow-up included weekly evaluations to day +100, fortnightly to month 6, then monthly. CMV/EBV PCR, blood counts, chimerism and GVHD assessments were performed centrally.</p><p>The primary endpoint was cumulative incidence of grade II-IV aGVHD during day 100, determined by the transplant specialist team in accordance with the Modified Glucksberg Grading. Secondary endpoints were grade III-IV aGVHD, chronic GVHD
结果显示,9/10 hla匹配组和10/10 hla匹配组的aGVHD和cGVHD发病率无统计学差异(图S2A-D)。巴昔昔单抗组3年OS为97.06%,对照组为92.23% (HR 0.37; p = 0.12)(表S1,图2A,D)。Basiliximab显著降低TRM (1.96% vs. 7.77%; HR 0.25; p = 0.05)(表S1,图2D,F)。在Basiliximab组中,有3例死亡,而对照组中有8例死亡(表S3)。尽管主要终点为阴性,但所有幸存者仍然不需要输血,这突出了令人鼓舞的临床趋势。总体感染发生率相似(Basiliximab 73.53% vs.对照组65.05%;OR 0.67; 0.37-1.22; p = 0.19)(表S1)。CMV再激活(34.31% vs. 33.98%)、EBV再激活(9.80% vs. 8.74%)、真菌感染(10.78% vs. 5.83%)、败血症(11.76% vs. 9.71%)和肺炎(18.63% vs. 13.59%)无差异(表S1)。Basiliximab组细菌感染发生率更高(56.86% vs. 41.75%; OR 0.54; 0.31-0.95; p = 0.03)(表S1)。静脉闭塞性疾病、出血性膀胱炎和自身免疫性细胞减少症的发生率在两组之间相似(表S1)。第一项随机对照试验表明,在第0天和第4天给予Basiliximab,加上标准的FK506/MTX/MMF预防,并不能显著降低重度地中海贫血MUD-HSCT后II-IV级或III-IV级aGVHD的发生。然而,该抗体是安全的,不会延迟植入,并显示出令人鼓舞的趋势,具有优越的TRM, OS和TFS。有几个因素可以解释这一消极的发现。首先,Basiliximab的给药方案(第0天和第4天20mg)是根据最初为预防肾移植排斥反应而制定的方案改编的。回顾性研究已经报道了该方案对MUDs或单倍异体造血干细胞移植患者预防GVHD的潜在益处[4,5]。然而,这些研究缺乏前瞻性随机化,导致证明同种异体造血干细胞移植剂量有效性的证据不足。一项使用更高剂量(第9天40毫克)的II期试验表明,为了达到最佳效果,可能需要其他给药策略。因此,目前的方案可能无法在aGVHD预防的关键窗口期维持足够的药物暴露。其次,Basiliximab靶向活化T细胞上IL-2受体的α链(CD25),从而抑制IL-2介导的供体源性活化T淋巴细胞的增殖,这是GVHD病理生理的核心[7-9]。然而,Basiliximab对静止T细胞没有作用,因为静止T细胞不表达cd25[8]。药代动力学数据表明,Basiliximab的半衰期约为6.5±2.1天,治疗血清浓度(0.2 μg/mL)在40mg剂量[10]后持续约26±8天。考虑到我们的队列中aGVHD的中位发病时间为+26天(范围为+9至+117天),目前的给药方案可能导致高危期的亚治疗药物水平。未来的研究应考虑调整剂量或时间以延长治疗暴露。尽管存在这些局限性,我们观察到次要结局的趋势令人鼓舞。整个队列的3年OS和TFS分别为94.63%和94.15%,与MSD移植报道的结果相当。虽然没有达到主要终点,但Basiliximab与OS (97.06% vs. 92.23%)和TFS (97.06% vs. 91.26%)改善相关,TRM改善更为显著(1.96% vs. 7.77%; HR 0.25; 0.07-0.85; p = 0.05)(虽然处于阈值,但有良好的趋势)。这些发现表明,可能通过降低高级别GVHD或其他免疫介导的毒性,对严重的移植相关并发症具有潜在的保护作用。尽管如此,II-IV级aGVHD(28.29%)和III-IV级aGVHD(11.71%)的发生率仍然高于我们之前的MSD-HSCT队列(分别为15.3%和6.0%),强调了GVHD在MUD环境中的持续挑战。这些比率与其他中心发表的数据一致,报道在接受MUD-HSCT的TM患者中,aGVHD发生率为20%-60%[1,2,11 -15]。因此,虽然Basiliximab没有达到预期的主要终点,但这些发现强调了修改方案以优化其免疫抑制效果的潜在临床益处,值得在未来的前瞻性试验中进一步研究。重要的是,Basiliximab耐受性良好,没有明显的输注相关不良事件。各组间中性粒细胞或血小板植入时间及总毒性均无差异。尽管细菌感染发生率有显著差异,但大多数都得到了及时有效的控制。 此外,其他感染并发症的发生率令人担忧,包括巨细胞病毒和EBV再激活、真菌感染、败血症或肺炎。这些数据支持Basiliximab在这种情况下的安全性,尽管其免疫抑制效力可能需要通过剂量或方案调整来增强。总之,虽然Basiliximab没有显著降低aGVHD的发病率,但它是安全的,耐受性良好,并与改善的TRM和生存结果相关。这些发现支持进一步研究优化剂量和时机策略,以最大限度地提高其在TM.Y.L的MUD-HSCT中的预防潜力。, Q.L和z.z设计了研究,访问并验证了数据,分析了结果。Z.W, r.l., L.S.对患者进行治疗,进行统计分析,并撰写论文。l.l., c.q., h.c., g.w., m.w., g.y., z.g., j.f., x.z., Y.C.对方案提出建议,治疗患者,分析结果,审稿。所有作者都可以访问统计报告,并且所有人都对提交出版的决定负有最终责任。广西医科大学青年领军人才培养计划(No. 202302)、广西医科大学先进创新团队与星虎学者计划、广西自然科学基金区域高发疾病研究联合项目(批准号:2023GXNSFAA026293)、国家卫生健康委地中海贫血医学重点实验室、广西地中海贫血研究重点实验室资助。所有程序均按有关准则执行。本研究经广西医科大学第一附属医院伦理委员会批准[批准文号:gxmuh-2014-14]。从患者处获得参与本研究的书面知情同意书。成人(≥18岁)自行完成知情同意书。对于未成年人(&lt; 18),由监护人代表参与本研究的未成年人提供知情同意书。发表同意:所有患者和监护人同意发表本研究。作者声明无利益冲突。如通讯作者提出合理要求,可提供原始数据用于学术研究。
{"title":"Basiliximab in the Prophylaxis of aGVHD for Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients With Thalassemia Major: A Prospective, Multicenter, Open-Label, Randomized Controlled Study","authors":"Zhenbin Wei,&nbsp;Rongrong Liu,&nbsp;Lingling Shi,&nbsp;Qiaochuan Li,&nbsp;Lianjin Liu,&nbsp;Baoshi Zheng,&nbsp;Chunjie Qin,&nbsp;Hong Chen,&nbsp;Guyun Wang,&nbsp;Meiqing Wu,&nbsp;Gaohui Yang,&nbsp;Ruolin Li,&nbsp;Zhaoping Gan,&nbsp;Qi Zhou,&nbsp;Jing Fan,&nbsp;Xuemei Zhou,&nbsp;Yinghua Chen,&nbsp;Zhiyu Zeng,&nbsp;Zhongming Zhang,&nbsp;Yongrong Lai","doi":"10.1002/ajh.70169","DOIUrl":"10.1002/ajh.70169","url":null,"abstract":"&lt;p&gt;We present the first prospective, multicenter, randomized controlled trial (RCT) evaluating Basiliximab prophylaxis for acute graft-versus-host disease (GVHD) in thalassemia major (TM) patients undergoing Matched unrelated donor hematopoietic stem-cell transplantation (MUD-HSCT). This study was registered at ClinicalTrials.gov [#NCT02342145]. This study addresses a critical unmet need in optimizing GVHD prevention strategies in this high-risk population.&lt;/p&gt;&lt;p&gt;Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains the only curative therapy currently available for thalassemia major (TM). While HLA-matched sibling-donor (MSD) transplantation yields &gt; 90% overall survival (OS) and &gt; 80% thalassemia-free survival (TFS), only 25%–30% of patients have available MSD [&lt;span&gt;1, 2&lt;/span&gt;]. Matched unrelated donor (MUD) transplantation thus represents a common alternative, but graft-versus-host disease, graft rejection and transplant-related mortality (TRM) remain obstacles.&lt;/p&gt;&lt;p&gt;Basiliximab, an IL-2 receptor (CD25) antagonist, has demonstrated efficacy in solid organ transplant rejection prophylaxis and in steroid-refractory aGVHD. Our trial rigorously compares standard GVHD prophylaxis with or without Basiliximab to clarify its prophylactic role in unrelated donor HSCT.&lt;/p&gt;&lt;p&gt;Three Chinese transplant centers enrolled patients (April 2015–September 2021) with transfusion-dependent TM, adequate organ function and no active infection or hepatitis. Key exclusions were HIV positivity, cytomegalovirus (CMV) or Epstein–Barr virus (EBV) viremia &gt; 200 copies/ml, or transaminases &gt; 4 × ULN. Written parental consent was obtained.&lt;/p&gt;&lt;p&gt;After eligibility confirmation, patients were sequentially numbered per center; alternate numbers were assigned to Basiliximab or control arms (open-label). All received identical myelo-ablative conditioning: fludarabine 50 mg/m&lt;sup&gt;2&lt;/sup&gt; days −12 to −10, busulfan 1 mg/kg q6 h days −9 to −6, cyclophosphamide 50 mg/kg days −5 to −2 and anti-thymocyte (ATG, Thymoglobulin) 2.5 mg/kg days −4 to −1. Hydroxyurea 30 mg/kg had been given for 2 months pre-conditioning. Peripheral-blood stem cells were infused from 10/10 or 9/10 HLA matching MUDs. GVHD prophylaxis in both arms consisted of tacrolimus (FK506 0.03 mg/kg/day, target 5–15 ng/mL) from day −3, methotrexate (15 mg/m&lt;sup&gt;2&lt;/sup&gt; day +1, 10 mg/m&lt;sup&gt;2&lt;/sup&gt; days +3, +6, +11) and mycophenolate mofetil (MMF 250 mg/day) for 90 days. Basiliximab-arm patients additionally received 10 mg (&lt; 35 kg) or 20 mg (≥ 35 kg) intravenously on days 0 and +4. Follow-up included weekly evaluations to day +100, fortnightly to month 6, then monthly. CMV/EBV PCR, blood counts, chimerism and GVHD assessments were performed centrally.&lt;/p&gt;&lt;p&gt;The primary endpoint was cumulative incidence of grade II-IV aGVHD during day 100, determined by the transplant specialist team in accordance with the Modified Glucksberg Grading. Secondary endpoints were grade III-IV aGVHD, chronic GVHD","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"628-632"},"PeriodicalIF":9.9,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70169","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Autoimmune Features in Sickle Cell Patients: A New Explanation for Liver Damage? 镰状细胞患者的自身免疫特征:肝损害的新解释?
IF 9.9 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-12-16 DOI: 10.1002/ajh.70168
Aude Mausoleo, Pascale Chretien, Astrid Laurent-Bellue, Laurence Rocher, Lisa Fredeau, Catherine Guettier, Paul-Albert Domnariu, Olivier Lambotte, Stephanie El Hajj, Chahinez Hani Dekimeche, Salima Hacein-Bey-Abina, Jean-Charles Duclos-Vallée, Christelle Chantalat-Auger, Eleonora De Martin, Nicolas Noel
<p>Biological features of autoimmunity seem to be particularly frequent in patients with sickle cell disease (SCD), although the pathophysiology of auto-antibody production and their clinical implications remain to be better characterized [<span>1</span>].</p><p>In our previous work, the presence of anti-liver antibodies appeared to be associated with a more severe phenotype of SCD. Noticeably, anti-LKM fluorescence in sickle cell patients was consistently described as atypical since they exhibited “liver microsome” type fluorescence as opposed to the bright, homogeneous liver staining seen in typical anti-LKM1 [<span>2</span>] (see Figure S1). No identification against cytochrome P450 could be demonstrated by Immunodot.</p><p>Other atypical anti-LKM antibodies have been described in the literature in various pathophysiological situations, with different fluorescence patterns and antigenic targets [<span>3</span>].</p><p>These observations raise questions about the pathophysiology of “atypical” anti-LKM development in the SCD population as compared to other pathological situations and their clinical implications.</p><p>We conducted a single-center study with retrospective data analysis covering an inclusion period from 2012 to 2022. We compared the clinical, biological, serological, radiological, and histological characteristics of 36 SCD patients with atypical anti-LKM antibodies (<i>SC + Ab +</i> group), comparing them with 36 SCD patients without biological autoimmunity matched on age, sex, and genotype (<i>SC + Ab-</i> group) and 38 nonsickle cell patients followed up at the referral center of liver diseases and having positive anti-LKM antibodies (<i>SC-Ab +</i> group).</p><p>For each patient, the data collected included: age, sex; history of chronic pathologies; personal and family history of autoimmune diseases; history of liver disease (cholecystectomy, liver transplantation, iron overload defined by serum ferritin > 1000 μg/L [<span>4</span>]); sickle cell genotype and treatment for SCD patients; history of alloimmunization; immunosuppressive therapy and its indication; biological markers of hepatic autoimmunity (the type and titer of autoantibodies and their appearance in indirect immunofluorescence); presence of other autoimmunity markers; results of biological liver tests at the time of anti-LKM sampling; serological results for the main hepatotropic viruses (IgG for human immunodeficiency virus (HIV), hepatitis A/B/C/E viruses (H(A/B/C/E)V), Epstein–Barr virus (EBV), cytomegalovirus (CMV), Parvovirus B19 (ParvoB19)); hepatic imaging studies (ultrasound, Magnetic Resonance Imaging [MRI]) and histological results of liver biopsy when available. We defined AIH according to the simplified IAIHG criteria [<span>5</span>].</p><p>Patient characteristics were presented as mean (standard deviation) or median (interquartile range) for continuous variables, depending on the distribution, and number (%) for categorical variables. Intergroup c
自身免疫的生物学特征似乎在镰状细胞病(SCD)患者中尤为常见,尽管自身抗体产生的病理生理学及其临床意义仍有待更好地表征。在我们之前的工作中,抗肝抗体的存在似乎与更严重的SCD表型相关。值得注意的是,镰状细胞患者的抗lkm荧光一直被描述为不典型,因为他们表现出“肝微粒体”型荧光,而不是典型的抗lkm1[2]中所见的明亮、均匀的肝脏染色(见图S1)。免疫点法未证实其对细胞色素P450的特异性。其他非典型抗lkm抗体已在文献中描述在各种病理生理情况下,具有不同的荧光模式和抗原靶点[3]。这些观察结果提出了与其他病理情况相比,SCD人群中“非典型”抗lkm发展的病理生理学及其临床意义的问题。我们进行了一项单中心研究,回顾性数据分析涵盖了2012年至2022年的纳入期。我们比较了36例非典型抗lkm抗体的SCD患者(SC + Ab +组)的临床、生物学、血清学、放射学和组织学特征,并将其与36例年龄、性别和基因型匹配的无生物自身免疫的SCD患者(SC + Ab-组)和38例在肝病转诊中心随访的抗lkm抗体阳性的非镰状细胞患者(SC-Ab +组)进行了比较。对于每位患者,收集的数据包括:年龄、性别;慢性病史;自身免疫性疾病的个人和家族史;肝脏病史(胆囊切除、肝移植、血清铁蛋白≥1000 μg/L[4]定义的铁超载);SCD患者镰状细胞基因型及治疗;同种异体免疫史;免疫抑制疗法及其适应症;肝脏自身免疫的生物学标志物(自身抗体的类型和滴度及其间接免疫荧光的表现);存在其他自身免疫标记物;抗lkm取样时肝脏生物检测结果;主要嗜肝病毒(人类免疫缺陷病毒(HIV) IgG、A/B/C/E型肝炎病毒(H(A/B/C/E)V)、eb病毒(EBV)、巨细胞病毒(CMV)、细小病毒B19 (ParvoB19))血清学检测结果;肝脏影像学检查(超声、磁共振成像[MRI])和肝活检组织学结果(如有)。我们根据简化的IAIHG标准[5]定义AIH。连续变量的患者特征表示为平均值(标准差)或中位数(四分位数范围),取决于分布,分类变量的数量(%)。根据分布情况,使用Student或Mann-Whitney检验对连续变量进行组间比较。根据不同的条件,通过Pearson的Chi-2检验或Fisher的精确检验来比较分类变量。统计学显著性阈值设为p &lt; 0.05。SC + Ab +患者以女性为主(72.2%),平均年龄33岁(±11.7岁),以SS基因型为主(94.4%)。32例患者(88.9%)接受SCD背景治疗,其中26例(72.2%)接受红细胞交换(RCE)计划。在SC + Ab +患者中,只有3例确诊为AIH(8.3%)。我们首先比较了SCD非典型抗lkm患者(SC + Ab+)与SC + Ab-对照组的特征(见表1)。在SCD的大多数慢性并发症方面,两组之间没有显著差异,但SC + Ab +组的铁超载发生率明显更高(50%比22.2%,p = 0.026)。SCD背景治疗的使用也有所不同,SC + Ab +组接受RCE计划的患者明显更多(72.2% vs. 44.4%, p = 0.017)。在自身免疫检查时,抗lkm组患者接受RCE计划的平均时间为4.3(±4.8)年,而SC + Ab组为2.9(±1.8)年。RCE每4-6周进行一次,主要用于复发性急性胸综合征(23例)、肺动脉高压(5例)、脑血管病(9例)和心脏病(2例)。HbS的典型目标是30%。生物学上,SC + Ab +组患者有更多的肝酶异常。平均LDH和血红蛋白水平在两组之间没有差异,但SC + Ab +患者的网红细胞计数更高(288.4 G/L vs 214.5 G/L, p = 0.023),总胆红素有显著差异,但结合胆红素没有显著差异,表明游离胆红素有差异,并指出更有效的溶血特征。主要嗜肝病毒血清阳性差异无统计学意义。 然后,我们比较了36例非典型抗lkm的SCD患者和38例在同一免疫学实验室鉴定的非典型抗lkm的年龄/性别控制的非镰状细胞患者的数据(见表1)。正如预期的那样,由于招募偏倚(肝移植中心),患者的背景不同,因为SC-Ab +组的大多数患者是移植受体(57.9%)。这也解释了长期免疫抑制剂使用方面的差异(SC-Ab +组为68.4%,主要是移植后皮质类固醇、他克莫司和MMF)。在SC-Ab +组中,有自身免疫性疾病史的患者也明显更多。相反,SC + Ab +患者有更多的脾切除术,更多的同种异体免疫,更多的输血后铁超载。两组在慢性器官并发症(肾病、心脏病)方面无差异。我们最后仔细研究了放射学和组织学数据。所有28例SCD患者的mri检查由三名不了解患者免疫状态的放射科医生进行审查(SC + Ab +组19例,SC + Ab-组9例)(见表S1)。MRI检查时的平均年龄和性别没有差异。我们通过定量方法(使用肝脏T2*多重梯度回波序列,计算肝脏的铁过载μmol/g)或通过“双序列”(梯度同相和非同相)磁共振成像的估计方法来评估铁过载,这表明同相图像上铁过载的信号强度与非同相图像相比降低(见图S3)。SC + Ab +组19例mri中有12例(63.2%)和SC + Ab-组9例mri中有4例(44.4%)出现铁超载。SC + Ab +组的9例(25%)患者和SC + Ab-组的1例(2.8%)患者可获得肝组织样本。病理小组对患者的自身免疫状态不知情,对每个标本进行检查(见表S2)。与SCD相关的肝脏病变,即伴有异常红细胞充血、凝集和肝窦周围纤维化的肝窦扩张几乎不变(见图S2)。另外,在9例SC + Ab +患者中有3例观察到结节性再生增生。9例SC + Ab +患者中有4例有门脉胆道型纤维化,其中2例有间隔,包括1例已知的硬化性胆管炎患者。9例SC + Ab +患者中有6例显示活性,大多数为轻度,其中2例伴有最小的浆细胞。组织学总铁评分差异很大(0 - 43)。有两名SC + Ab +患者完全呈阴性。9例SC + Ab +患者中有2例(5%)脂肪变性基本不存在或极少发生。在这项研究中,我们发现非典型抗lkm的SCD患者有更多的溶血标志物(更高的网织网细胞计数和更高的胆红素水平),更频繁的长期RCE计划(72.2% vs. 44.4%),更多的铁超载(50% vs. 22.2%),以及更多的肝功能测试紊乱,即使没有明显的AIH,这表明这些抗体的存在,SCD的活性及其治疗之间存在联系。值得注意的是,大多数非典型抗lkm患者没有明确的自身免疫性肝炎,在我们的研究中,74例抗lkm阳性患者中只有7例确诊为AIH,其中包括SCD组的3例。我们观察到患有抗lkm的SCD患者比没有自身免疫的患者更有可能接受RCE计划。一种假设可能是一种更活跃的疾病,证明需要加强SCD治疗。在之前的一项对266例SCD患者的队列研究中,我们发现肝自身免疫患者的SCD活动评分高于无自身免疫患者。在本研究中,SC + Ab +组有一些溶血标志物的水平升高,如更高的网织红细胞计数(但相同的Hb水平)和更高的总胆红素,而结合胆红素没有差异。因此,抗lkm抗体的产生可能与伴有更多溶血及其慢性并发症(即更多炎症和更多慢性血管病变)的SCD的活性有关。另一种假说可能是反复输血引
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引用次数: 0
Real‐World Outcomes and Treatment Patterns in Patients With Acute Myeloid Leukemia and TP53 Gene Mutation or 17p Deletion 急性髓性白血病患者TP53基因突变或17p缺失的现实世界结果和治疗模式
IF 12.8 1区 医学 Q1 HEMATOLOGY Pub Date : 2025-12-13 DOI: 10.1002/ajh.70165
Rebecca Bystrom, Laura L. Fernandes, Joseph Wynne, Dianne Pulte, Eric Hansen, Andrew J. Belli, Anna Barcellos, Christina M. Zettler, Jonathon Vallejo, Wenjuan Gu, Angelo DeClaro, Catherine C. Lerro, Ching‐Kun Wang, Donna R. Rivera, Kelly J. Norsworthy
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引用次数: 0
期刊
American Journal of Hematology
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