Paola Quarello, Karim Karimi, Slavica Trajkova, Emanuela Garelli, Mehdi Samadieh, Emanuela Iovino, Tommaso Pippucci, Giovanni Papagni, Sandra Dalfonso, Lucia Corrado, Serena Rizzo, Adriana Carando, Jennifer Kerkhof, Jessica Rzasa, Haley McConkey, Michael Levy, Marco Zecca, Francesca Fioredda, Angelica Barone, Simone Cesaro, Maria Gabelli, Francesca Torchio, Giulia Zucchetti, Maria Elena Cantarini, Paola Corti, Ugo Ramenghi, Franco Locatelli, Franca Fagioli, Bekim Sadikovic, Alfredo Brusco
Diamond-Blackfan Anemia Syndrome (DBAS) is a rare inherited bone marrow failure syndrome (IBMFS) characterized by impaired erythropoiesis and significant genetic heterogeneity. Diagnosis can be challenging due to clinical variability and the lack of sensitive and specific biomarkers. We investigated the evidence for a DNA methylation (DNAm) episignature in a cohort of 80 DBAS patients with causative variants in various ribosomal protein genes: DBA1 (RPS19, n = 30), DBA4 (RPS17, n = 6), DBA5 (RPL35A, n = 8), DBA6 (RPL5, n = 15), DBA7 (RPL11, n = 13), DBA10 (RPS26, n = 8). We identified a distinct and highly accurate episignature biomarker for DBAS, clearly differentiating it from both Fanconi anemia and a broad spectrum of other episignature-positive disorders. Furthermore, we developed a specific DNAm classifier for the clinically similar DBA6 and DBA7 subtypes. Applying the DBAS episignature analysis to six molecularly uncharacterized cases, three exhibited the DBAS pattern. Subsequent genome sequencing identified causative genetic variants in two (RPL5: c.325-380A>G:p.?; RPL26: c.-6 + 3_-6 + 25del:p.?), validating the test robustness. Methylation profiles from two revertant cases (RPS19:P47L and RPS17 full gene deletion) exhibited the DBAS episignature, suggesting it to be a stable epigenetic mark associated with the underlying genetic mutation, likely established early in development. In conclusion, we propose DNAm profiling as a robust diagnostic tool for DBAS, providing a biomarker applicable to all patients with clinical suspicion of the disease and critically aiding in the resolution of variants of uncertain significance and molecularly uncharacterized cases.
Diamond‐Blackfan贫血综合征（DBAS）是一种罕见的遗传性骨髓衰竭综合征（IBMFS），其特征是红细胞功能受损和显著的遗传异质性。由于临床变异性和缺乏敏感和特异性的生物标志物，诊断可能具有挑战性。我们研究了80名具有不同核糖体蛋白基因致病变异的DBA1 （RPS19, n = 30）、DBA4 （RPS17, n = 6）、DBA5 （RPL35A, n = 8）、DBA6 （RPL5, n = 15）、DBA7 （RPL11, n = 13）、DBA10 （RPS26, n = 8）的dbaas患者的DNA甲基化（DNAm）显著特征的证据。我们确定了一种独特且高度准确的DBAS表观特征生物标志物，将其与范可尼贫血和其他广泛的表观特征阳性疾病区分开来。此外，我们为临床相似的DBA6和DBA7亚型开发了一种特异性的DNAm分类器。将dba附加特征分析应用于6个分子特征不明确的案例，其中3个表现出了dba模式。随后的基因组测序确定了两个致病基因变异（RPL5: c.325‐380A>G:p.?; RPL26: c.‐6 + 3_‐6 + 25del:p.?），验证了测试的稳健性。来自两个反向病例（RPS19:P47L和RPS17全基因缺失）的甲基化谱显示出DBAS表观特征，表明它是与潜在基因突变相关的稳定表观遗传标记，可能在发育早期建立。总之，我们建议DNAm分析作为一种强大的DBAS诊断工具，提供一种适用于所有临床怀疑该疾病的患者的生物标志物，并有助于解决不确定意义的变异和分子未表征的病例。
{"title":"DNA Methylation Episignature as a Novel Diagnostic Tool for Diamond-Blackfan Anemia Syndrome","authors":"Paola Quarello, Karim Karimi, Slavica Trajkova, Emanuela Garelli, Mehdi Samadieh, Emanuela Iovino, Tommaso Pippucci, Giovanni Papagni, Sandra Dalfonso, Lucia Corrado, Serena Rizzo, Adriana Carando, Jennifer Kerkhof, Jessica Rzasa, Haley McConkey, Michael Levy, Marco Zecca, Francesca Fioredda, Angelica Barone, Simone Cesaro, Maria Gabelli, Francesca Torchio, Giulia Zucchetti, Maria Elena Cantarini, Paola Corti, Ugo Ramenghi, Franco Locatelli, Franca Fagioli, Bekim Sadikovic, Alfredo Brusco","doi":"10.1002/ajh.70141","DOIUrl":"10.1002/ajh.70141","url":null,"abstract":"<p>Diamond-Blackfan Anemia Syndrome (DBAS) is a rare inherited bone marrow failure syndrome (IBMFS) characterized by impaired erythropoiesis and significant genetic heterogeneity. Diagnosis can be challenging due to clinical variability and the lack of sensitive and specific biomarkers. We investigated the evidence for a DNA methylation (DNAm) episignature in a cohort of 80 DBAS patients with causative variants in various ribosomal protein genes: DBA1 (<i>RPS19</i>, <i>n</i> = 30), DBA4 (<i>RPS17</i>, <i>n</i> = 6), DBA5 (<i>RPL35A</i>, <i>n</i> = 8), DBA6 (<i>RPL5</i>, <i>n</i> = 15), DBA7 (<i>RPL11</i>, <i>n</i> = 13), DBA10 (<i>RPS26</i>, <i>n</i> = 8). We identified a distinct and highly accurate episignature biomarker for DBAS, clearly differentiating it from both Fanconi anemia and a broad spectrum of other episignature-positive disorders. Furthermore, we developed a specific DNAm classifier for the clinically similar DBA6 and DBA7 subtypes. Applying the DBAS episignature analysis to six molecularly uncharacterized cases, three exhibited the DBAS pattern. Subsequent genome sequencing identified causative genetic variants in two (<i>RPL5</i>: c.325-380A>G:p.?; <i>RPL26</i>: c.-6 + 3_-6 + 25del:p.?), validating the test robustness. Methylation profiles from two revertant cases (<i>RPS19</i>:P47L and <i>RPS17</i> full gene deletion) exhibited the DBAS episignature, suggesting it to be a stable epigenetic mark associated with the underlying genetic mutation, likely established early in development. In conclusion, we propose DNAm profiling as a robust diagnostic tool for DBAS, providing a biomarker applicable to all patients with clinical suspicion of the disease and critically aiding in the resolution of variants of uncertain significance and molecularly uncharacterized cases.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 2","pages":"228-241"},"PeriodicalIF":9.9,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70141","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145532095","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}
<p>Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a fatal thrombotic microangiopathy (TMA) caused by autoantibodies against disintegrin and metalloprotease with thrombospondin type 1 motif member 13 (ADAMTS13) [<span>1</span>]. Until recently, the standard treatments for iTTP were therapeutic plasma exchange (TPE) and immunosuppression. Caplacizumab, a humanized nanobody targeting the A1 domain of von Willebrand factor (VWF), demonstrated superiority over placebo in faster normalization of platelet count, a reduction in the composite endpoint (TTP-related death, exacerbation, or at least one thrombotic event), and a decrease in the need for TPE in an integrated analysis of the phase 2 and 3 trials for acute iTTP [<span>2</span>]. Treatment evaluation in the era of caplacizumab was proposed by the International Working Group (IWG) for iTTP [<span>3</span>]. Updated definitions for exacerbation and remission were evaluated based on the suspension of both TPE and anti-VWF therapy, namely, caplacizumab. However, thrombocytopenic events during caplacizumab administration have not yet been analyzed so far. This correspondence reports the findings of our study on the frequency of thrombocytopenic events and their association with relevant clinical parameters in caplacizumab-treated Japanese acute iTTP patients.</p><p>Briefly, 33 episodes in 31 Japanese patients with acute iTTP who were administered caplacizumab between December 2022 and February 2024 were identified in the Nara Medical University Registry on TMA [<span>4</span>]. iTTP diagnosis was as follows: (1) hemolytic anemia and thrombocytopenia, (2) severely decreased ADAMTS13 activity (< 10%), and (3) presence of detectable ADAMTS13 inhibitor (≥ 0.5 Bethesda units [BU]/mL) [<span>5</span>]. Recurrent thrombocytopenia was defined as a decrease in the platelet count to < 150 × 10<sup>9</sup>/L during caplacizumab therapy after initially achieving a clinical response (CR) with a platelet count of ≥ 150 × 10<sup>9</sup>/L. Twenty patients met the criteria for recurrent thrombocytopenia (thrombocytopenia group), whereas the remaining patients were classified into the non-thrombocytopenia group. Additionally, we defined the event at which the platelet count reached its lowest point after achieving CR as the second dip (Figure S1). Of the 20 patients, 9 underwent intensified treatment, such as TPE or immunosuppressive therapies (intensified treatment group); the remaining 11 patients were classified into the non-intensified treatment group (Figure S2).</p><p>Citrated patient plasma samples taken at diagnosis or during the treatment course were prepared and stored at −30°C until analysis. A sensitive chromogenic enzyme-linked immunosorbent assay (ELISA) was used to measure ADAMTS13 activity (Kainos Laboratories, Tokyo, Japan) [<span>6</span>]. ADAMTS13 inhibitor titer was evaluated using a plasma mixing assay (Bethesda assay); a titer of ≥ 0.5 BU/mL was considered positive. Anti-ADA
免疫介导的血栓性血小板减少性紫癜（iTTP）是一种致命的血栓性微血管病（TMA），由抗崩解素和具有血小板反应蛋白1型基元13 (ADAMTS13)[1]的金属蛋白酶自身抗体引起。直到最近，iTTP的标准治疗是治疗性血浆交换（TPE）和免疫抑制。Caplacizumab是一种针对血管性血血病因子（VWF） A1结构域的人源化纳米体，在急性iTTP bbb的2期和3期试验的综合分析中显示，与安慰剂相比，Caplacizumab在血小板计数更快正常化、复合终点（ttp相关死亡、恶化或至少一个血栓形成事件）减少以及TPE需求减少方面具有优势。卡普拉珠单抗时代的治疗评价由iTTP bbb国际工作组（IWG）提出。根据暂停TPE和抗vwf治疗（即卡普拉珠单抗）来评估恶化和缓解的最新定义。然而，目前尚未分析卡普拉珠单抗给药期间的血小板减少事件。本文报道了我们对卡帕单抗治疗的日本急性iTTP患者血小板减少事件的频率及其与相关临床参数的关系的研究结果。简而言之，在奈良医科大学TMA注册表中，在2022年12月至2024年2月期间，31名接受卡普拉珠单抗治疗的日本急性iTTP患者中发现了33次发作。iTTP诊断如下：(1)溶血性贫血和血小板减少症；(2)ADAMTS13活性严重降低（< 10%）；(3)存在可检测到的ADAMTS13抑制剂（≥0.5 Bethesda单位[BU]/mL）[5]。复发性血小板减少被定义为在卡普拉珠单抗治疗期间，血小板计数在最初达到临床缓解（CR）且血小板计数≥150 × 109/L后，血小板计数下降至150 × 109/L。20例患者符合复发性血小板减少的标准（血小板减少组），其余患者分为非血小板减少组。此外，我们将达到CR后血小板计数达到最低点的事件定义为第二次下降（图S1）。20例患者中，9例接受强化治疗，如TPE或免疫抑制治疗（强化治疗组）；其余11例患者分为非强化治疗组（图S2）。在诊断时或治疗过程中采集的柠檬酸患者血浆样品制备并保存在- 30°C，以待分析。采用灵敏的显色酶联免疫吸附法（ELISA）测定ADAMTS13的活性（Kainos Laboratories, Tokyo, Japan）。使用血浆混合试验（Bethesda试验）评估ADAMTS13抑制剂滴度；滴度≥0.5 BU/mL为阳性。采用TECHNOZYM ADAMTS13 INH酶联免疫吸附测定试剂盒（Technoclone，维也纳，奥地利）检测抗ADAMTS13 IgG水平。采用自动凝血分析仪CN-3000 （Sysmex, Kobe, Japan）检测VWF抗原（VWF:Ag）和VWF里斯托素辅因子活性（VWF:RCo） （Siemens Healthineers）。在以下时间点对ADAMTS13和VWF相关参数进行时程评估：(1)首次就诊，(2)血小板计数≥150 × 109/L的初始CR，(3)第二次下降，(4)卡placizumab治疗结束时，(5)卡placizumab治疗结束后1周（图S1）。分析从第一次TPE到ADAMTS13活性持续≥10%的时间与初始ADAMTS13抑制剂和抗ADAMTS13 IgG水平的相关性。分类变量以频率表示，连续变量以四分位数范围的中位数表示。组间比较采用Fisher精确检验或Mann-Whitney U检验，时间变化采用Friedman检验，相关性采用Spearman秩检验。P &; 0.05 b0；采用EZR[7]进行分析。总的来说，31例经卡普拉珠单抗治疗的急性iTTP患者的33次发作被纳入评估。20例血小板减少组患者中有17例和13例非血小板减少组患者中有12例在首次iTTP发作时入组。我们回顾性比较了有血小板减少症和无血小板减少症患者的临床特征、实验室参数和治疗方法的差异（表S1）。两组间的实验室数据、初始神经症状的比例和治疗方法无显著差异。所有患者均达到cr。将血小板减少患者分为强化组（n = 9）和非强化组（n = 11）。临床参数及治疗详情见表1。 在强化治疗组，主要针对复发性血小板减少需要额外的治疗，包括TPE （n = 4）、FFP输注（n = 1）、利妥昔单抗（n = 3）、强的松龙脉冲治疗（n = 2）和环磷酰胺（n = 2）（表S2）。Bethesda法测定的ADAMTS13抑制剂初始滴度中位数在强化治疗组显著升高（13.5比4.6 BU/mL, p = 0.015），而初始抗ADAMTS13 IgG水平无显著差异。强化治疗组初始VWF:RCo/VWF:Ag中位数较低（0.38 vs. 0.62, p = 0.026）。TPE疗程的次数和利妥昔单抗的比例或时间在两组之间具有可比性。相比之下，强化治疗组达到ADAMTS13活性≥10%的中位时间（43天对19天，p = 0.003）和卡普拉珠单抗治疗的持续时间（47天对36天，p = 0.014）明显更长。接下来，我们比较了两组之间第二次下降时的实验室参数。强化治疗组第二次血小板计数中位数显著低于强化治疗组（66 × 109/L vs. 109 × 109/L, p = 0.018）。血红蛋白和乳酸脱氢酶水平各组间无显著差异。相比之下，强化组ADAMTS13活性中位数显著降低（0.5% vs. 23.7%, p = 0.015）， ADAMTS13抑制剂滴度中位数（3.6 vs. < 0.5 BU/mL, p = 0.036）和抗ADAMTS13 IgG抗体水平中位数（69.3 vs. 8.0 U/mL, p = 0.012）均显著升高。分别评估强化治疗组和非强化治疗组VWF:RCo和VWF:Ag水平的变化（图1）。在治疗期间几乎所有时间点，两组的VWF:RCo均降至定量下限（12.13%）。在强化组中，这两个参数随时间变化显著，没有两两变化，而在治疗期间，它们低于基线或非强化组的治疗后。在本研究纳入的所有患者中，初始ADAMTS13抑制剂滴度与首次TPE至ADAMTS13活性≥10%的时间呈正相关（r = 0.672, p < 0.001）（图S3A），而与初始抗ADAMTS13 IgG水平的相关性为0.388 (n = 30, p = 0.034)（图S3B）。在卡普拉单抗治疗的iTTP患者中，超过一半的患者观察到复发性血小板减少。一些患者接受了额外的治疗，如重新开始血浆置换或增强免疫抑制。2021年IWG共识报告将临床结果重新定义为：临床恶化为停止TPE或抗vwf治疗后30天内血小板计数下降150 × 109/L，临床复发为临床缓解后记录的严重ADAMTS13缺乏症的类似下降。然而，在我们的研究中观察到的卡普拉珠单抗期间复发性血小板减少症未被纳入，也未提出任何管理策略。值得注意的是，在现实世界中关于卡普拉珠单抗使用的报告中，只有德国-奥地利组记录了约10%的一线病例在使用卡普拉珠单抗期间病情加重。在需要强化治疗的复发性血小板减少病例中，与未强化治疗组相比，患者在第二次滴注时血小板计数下降更明显，ADAMTS13活性降低，ADAMTS13抑制剂滴度更高。这些患者在发病时抑制剂滴度也较高，ADAMTS13恢复延迟，表明iTTP的免疫状态
{"title":"Recurrent Thrombocytopenia During Caplacizumab Therapy in Acute Immune-Mediated Thrombotic Thrombocytopenic Purpura","authors":"Kenki Saito, Kazuya Sakai, Atsushi Hamamura, Hidekazu Azumi, Masayuki Kubo, Makoto Osada, Hideo Yagi, Shogo Murata, Masashi Nishikubo, Daichi Nishiyama, Yasunori Ueda, Masanori Matsumoto","doi":"10.1002/ajh.70139","DOIUrl":"10.1002/ajh.70139","url":null,"abstract":"<p>Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a fatal thrombotic microangiopathy (TMA) caused by autoantibodies against disintegrin and metalloprotease with thrombospondin type 1 motif member 13 (ADAMTS13) [<span>1</span>]. Until recently, the standard treatments for iTTP were therapeutic plasma exchange (TPE) and immunosuppression. Caplacizumab, a humanized nanobody targeting the A1 domain of von Willebrand factor (VWF), demonstrated superiority over placebo in faster normalization of platelet count, a reduction in the composite endpoint (TTP-related death, exacerbation, or at least one thrombotic event), and a decrease in the need for TPE in an integrated analysis of the phase 2 and 3 trials for acute iTTP [<span>2</span>]. Treatment evaluation in the era of caplacizumab was proposed by the International Working Group (IWG) for iTTP [<span>3</span>]. Updated definitions for exacerbation and remission were evaluated based on the suspension of both TPE and anti-VWF therapy, namely, caplacizumab. However, thrombocytopenic events during caplacizumab administration have not yet been analyzed so far. This correspondence reports the findings of our study on the frequency of thrombocytopenic events and their association with relevant clinical parameters in caplacizumab-treated Japanese acute iTTP patients.</p><p>Briefly, 33 episodes in 31 Japanese patients with acute iTTP who were administered caplacizumab between December 2022 and February 2024 were identified in the Nara Medical University Registry on TMA [<span>4</span>]. iTTP diagnosis was as follows: (1) hemolytic anemia and thrombocytopenia, (2) severely decreased ADAMTS13 activity (< 10%), and (3) presence of detectable ADAMTS13 inhibitor (≥ 0.5 Bethesda units [BU]/mL) [<span>5</span>]. Recurrent thrombocytopenia was defined as a decrease in the platelet count to < 150 × 10<sup>9</sup>/L during caplacizumab therapy after initially achieving a clinical response (CR) with a platelet count of ≥ 150 × 10<sup>9</sup>/L. Twenty patients met the criteria for recurrent thrombocytopenia (thrombocytopenia group), whereas the remaining patients were classified into the non-thrombocytopenia group. Additionally, we defined the event at which the platelet count reached its lowest point after achieving CR as the second dip (Figure S1). Of the 20 patients, 9 underwent intensified treatment, such as TPE or immunosuppressive therapies (intensified treatment group); the remaining 11 patients were classified into the non-intensified treatment group (Figure S2).</p><p>Citrated patient plasma samples taken at diagnosis or during the treatment course were prepared and stored at −30°C until analysis. A sensitive chromogenic enzyme-linked immunosorbent assay (ELISA) was used to measure ADAMTS13 activity (Kainos Laboratories, Tokyo, Japan) [<span>6</span>]. ADAMTS13 inhibitor titer was evaluated using a plasma mixing assay (Bethesda assay); a titer of ≥ 0.5 BU/mL was considered positive. Anti-ADA","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 2","pages":"356-360"},"PeriodicalIF":9.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498666","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}
Matthew J. Rees, Jack Khouri, Ariel F. Grajales-Cruz, Saurabh S. Zanwar, Utkarsh Goel, Shonali Midha, Julian Kelley, Omar Castaneda Puglianini, Andre De Menezes Silva Corraes, Shahzad Raza, James A. Davis, Kimberly Green, Doris K. Hansen, Rahul Banerjee, Surbhi Sidana, Krina K. Patel, Giada Bianchi, Douglas W. Sborov, Sarah Lee, Shaji K. Kumar, Rachid Baz, Faiz Anwer, Lekha Mikkilineni, Omar Nadeem, Yi Lin, Larry D. Anderson Jr
<p>Systemic light-chain (AL) amyloidosis is a plasma cell neoplasm characterized by the production of aberrant light chains which misfold and accumulate to cause progressive organ damage. Plasma cell-directed therapy to curtail amyloidogenic light-chain production and permit organ recovery is central to management. The effectiveness of therapy is measured by the extent of clonal free light-chain (FLC) reduction defined by the hematological response criteria, with complete responses (CR) associated with improved organ recovery and survival [<span>1</span>].</p><p>Despite the introduction of daratumumab for newly diagnosed AL amyloidosis, disease responses are suboptimal in approximately 50% of cases, and many later relapse [<span>2, 3</span>]. Bispecific T-cell engagers (TCE) have produced unprecedented outcomes in relapsed multiple myeloma (MM), and whether they can be safely applied to AL amyloidosis is a key clinical question. To date, evidence for TCE in AL amyloidosis is limited to small case series, and their safety—with regard to cytokine release syndrome (CRS), infections, and early organ deterioration in this vulnerable population—remains poorly defined [<span>4-6</span>].</p><p>This retrospective study evaluated all AL amyloidosis patients who received TCE therapy targeting BCMA or GPRC5D between February 2023 and March 2025. Data were collected from nine United States (US) academic centers participating in the US MM Immunotherapy Consortium. Each center obtained Institutional Review Board approval for participation. Dosing followed prescribing information; during step-up, subsequent therapy was at the discretion of the treating physician. Talquetamab was dosed according to the biweekly dosing schedule.</p><p>CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the American Society for Transplantation and Cellular Therapy criteria [<span>7</span>]. Hematologic toxicities were graded according to the Common Terminology Criteria for Adverse Events, v5.0. Infectious disease prophylaxis, use of growth colony-stimulating factor, and treatment of CRS and ICANS were according to institutional guidelines [<span>8</span>]. Hematologic responses were defined according to consensus response criteria [<span>1</span>]. Cardiac and renal responses were defined according to the graded response criteria [<span>9</span>], and cardiac stage per the European modification of the Mayo 2004 model [<span>10</span>]. Data were analyzed using ‘<i>R</i>’ v4.3.2.</p><p>Twenty-nine patients with AL amyloidosis treated with TCEs were included: teclistamab (<i>n</i> = 19), elranatamab (<i>n</i> = 6), and talquetamab (<i>n</i> = 4). Baseline patient, disease and treatment characteristics are summarized in Table 1. The median age was 72 years (IQR: 66–75), with a female predominance (59%). Cardiac stage prior to TCE was known in 26 patients; 2 patients were stage 3A (8%), and 5 patients were stage 3B (19%). Most patients had l
系统性轻链（AL）淀粉样变性是一种浆细胞肿瘤，其特征是产生异常的轻链，这些轻链错误折叠和积聚导致进行性器官损害。浆细胞定向治疗减少淀粉样蛋白轻链的产生并允许器官恢复是治疗的核心。治疗的有效性是通过血液学反应标准定义的克隆游离轻链（FLC）减少程度来衡量的，完全缓解（CR）与器官恢复和生存期的改善相关。尽管引入了daratumumab治疗新诊断的AL淀粉样变性，但大约50%的病例的疾病反应不理想，许多病例后来复发[2,3]。双特异性t细胞结合剂（TCE）在复发性多发性骨髓瘤（MM）治疗中产生了前所未有的效果，它们是否可以安全地应用于AL淀粉样变性是一个关键的临床问题。迄今为止，TCE在AL淀粉样变中的证据仅限于小病例系列，其安全性-关于细胞因子释放综合征（CRS），感染和易感人群的早期器官退化-仍然不明确[4-6]。这项回顾性研究评估了2023年2月至2025年3月期间接受针对BCMA或GPRC5D的TCE治疗的所有AL淀粉样变性患者。数据来自参加美国MM免疫治疗联盟的9个美国学术中心。每个中心都获得了机构审查委员会的批准。按照处方信息给药；在升级过程中，后续治疗由主治医师决定。Talquetamab按照两周给药计划给药。CRS和免疫效应细胞相关神经毒性综合征（ICANS）根据美国移植和细胞治疗学会标准[7]进行分级。血液学毒性根据不良事件通用术语标准v5.0进行分级。传染病预防、生长集落刺激因子的使用以及CRS和ICANS的治疗均按照机构指南bbb进行。血液学反应根据一致反应标准[1]定义。根据分级反应标准[9]定义心脏和肾脏反应，根据Mayo 2004模型的欧洲修订[10]定义心脏分期。使用‘ R ’ v4.3.2对数据进行分析。纳入29例接受TCEs治疗的AL淀粉样变性患者：特司他单抗（n = 19）、埃尔那他单抗（n = 6）和塔克他单抗（n = 4）。基线患者、疾病和治疗特征总结于表1。中位年龄为72岁（IQR: 66-75），以女性为主（59%）。26例患者已知TCE前的心脏分期；2例为3A期（8%），5例为3B期（19%）。大多数患者为λ轻链同型（59%）；31%发生t（11;14）易位。6例患者诊断性骨髓浆细胞（BMPC）负荷未知。在剩余的患者中，65%的患者BMPCs≥20%。10名患者（34%）在诊断时BMPCs≥60%，或TCE前FLC比值≥100。8例患者先前接受过bcma定向治疗（n = 4抗体药物偶联物[ADC]， n = 3 CAR T, n = 1 ADC + TCE）。至于器官受累，66%为心脏受累，59%为肾脏受累。45%的患者发生CRS(1级，n = 8； 2级，n = 5；≥3级，n = 0)， 14%的患者发生ICANS（1级，n = 3； 2级，n = 1；≥3级，n = 0）。7例患者接受tocilizumab治疗；1例患者接受预防性tocilizumab治疗。按TCE划分的CRS率见图S1。第1周期无患者需要入住重症监护病房。CRS的发病是双峰的，41%发生在第2天，23%发生在第5天。20名患者（69%）接受了免疫球蛋白预防；开始IVIg的中位时间为28天（IQR 18,63）。10例患者感染≥1级，其中6例感染≥3级；研究期间共发生17次感染事件（11次细菌感染，6次病毒感染）。IVIg开始后，≥3级感染率为25%（5/20）。在25例有完整血液学不良事件数据的患者中，治疗后出现≥3级贫血、血小板减少和中性粒细胞减少的患者分别占8%、20%和20%。血液学总缓解率（ORR）为76%，包括66% CR， 7%非常好部分缓解（VGPR）和3%部分缓解（PR）。2例患者未接受疾病重新评估；1例如下所述的治疗早期出现的死亡，1例在第2周期之前失去随访。TCE的ORR如图S2所示。6例患者进行了下一代流式细胞术可测量残留疾病（MRD）评估，所有患者均获得MRD阴性。在应答者中，达到VGPR或更好的中位时间为29天（IQR: 18,56）。在先前接受BCL2抑制剂治疗的4例t（11;14）患者中，TCE治疗的ORR为75%。 游泳者图1描述了接受的TCE、血液学反应时间和生存率。在接受TCE治疗时符合心脏反应评估条件的14例患者中（升高的b型利钠肽[BNP] >； 150 ng/L或n端前BNP >； 650 ng/L）， 64%的患者获得了反应（心脏PR， n = 4；心脏VGPR， n = 2；心脏CR， n = 3）。通过Kaplan-Meier方法，达到心脏反应的中位时间为4.6个月（95% CI 2.7-未达到）。在TCE开始时符合肾反应评估条件的4例患者（基线时1 g/天蛋白尿）中，所有患者均获得反应（肾PR， n = 1；肾VGPR， n = 2；肾CR， n = 1），中位肾反应时间为3.8个月（95% CI 0.7-未达到）。符合条件的患者6个月标志性器官反应率心脏为57%，肾脏为75%。中位随访时间为8.8个月，1年总生存率为77% (95% CI: 62%-95%)（图2）。6人死亡，其中4人在TCE治疗期间死亡。1例心脏受累患者（Mayo 2004年IIIB期）在替司他单增加剂量期间（第1周期，第2天）出现心室颤动停搏，无CRS特征。一名没有心脏或肾脏受累的患者在开始服用talquetamab 2个月后死于细菌性败血症。一例骨髓瘤并发患者的死亡是由于特司他单疗程1后骨髓瘤进行性高钙血症和急性肾损伤，一例心脏和肾脏受累的患者在骨折手术固定术中死亡。其余2例死亡发生在治疗结束后：1例原因不明，1例心脏受累患者在停用替司他单抗3个月后死于心力衰竭，尽管获得了血液学cr。这项研究代表了TCE治疗AL淀粉样变性的最大队列研究。TCE诱导了高比率的快速和深度血液学反应，这些反应通常伴随着早期器官反应。尽管心脏和肾脏受累的发生率很高，但CRS的发生率很低，没有≥3级的事件。相比之下，感染性并发症的发生率与TCE的广泛应用一致。非复发死亡率（NRM）主要反映了该队列的疾病晚期，有2例死亡（7%）归因于心脏原因，但罕见的致命治疗相关事件继发于CRS或感染。TCE的显著疗效从MM扩展到AL淀粉样变性。从生物学角度来看，AL淀粉样变性的惰性、低肿瘤负荷的浆细胞克隆特征可能更容易发生TCE，这在低疾病负荷环境中非常有效[11,12]。我们的研究结果和其他现实世界的经验支持这一点；teclistamab的两个病例系列显示ORR在88%至100%之间，而elranatamab的一系列病例显示ORR为100%，CR率为67%[4-6]。这些结果与复发性淀粉样变性的替代疗法相比是有利的；相比之下，泊马度胺、贝兰他单抗马福多汀和卡非佐米在达拉单抗naïve人群中产生≥29%-46%的VGPR率[13-15]。与FLC根除的深度和速度一致，我们观察到在新诊断疾病中，早期器官反应接近达拉图单抗-硼替佐米-环磷酰胺-地塞米松的报告；在该研究中，6个月心脏和肾脏反应分别为42%和54%，而在我们的队列中，这两个数据分别为57%和75%，尽管数据有限[2,3]。我们对暴露于BCL2抑制的t（11;14）患者75%的ORR也支持TCE作为venet
{"title":"The Real-World Safety and Efficacy of Bispecific T-Cell Engager Therapy in Systemic AL Amyloidosis","authors":"Matthew J. Rees, Jack Khouri, Ariel F. Grajales-Cruz, Saurabh S. Zanwar, Utkarsh Goel, Shonali Midha, Julian Kelley, Omar Castaneda Puglianini, Andre De Menezes Silva Corraes, Shahzad Raza, James A. Davis, Kimberly Green, Doris K. Hansen, Rahul Banerjee, Surbhi Sidana, Krina K. Patel, Giada Bianchi, Douglas W. Sborov, Sarah Lee, Shaji K. Kumar, Rachid Baz, Faiz Anwer, Lekha Mikkilineni, Omar Nadeem, Yi Lin, Larry D. Anderson Jr","doi":"10.1002/ajh.70140","DOIUrl":"10.1002/ajh.70140","url":null,"abstract":"<p>Systemic light-chain (AL) amyloidosis is a plasma cell neoplasm characterized by the production of aberrant light chains which misfold and accumulate to cause progressive organ damage. Plasma cell-directed therapy to curtail amyloidogenic light-chain production and permit organ recovery is central to management. The effectiveness of therapy is measured by the extent of clonal free light-chain (FLC) reduction defined by the hematological response criteria, with complete responses (CR) associated with improved organ recovery and survival [<span>1</span>].</p><p>Despite the introduction of daratumumab for newly diagnosed AL amyloidosis, disease responses are suboptimal in approximately 50% of cases, and many later relapse [<span>2, 3</span>]. Bispecific T-cell engagers (TCE) have produced unprecedented outcomes in relapsed multiple myeloma (MM), and whether they can be safely applied to AL amyloidosis is a key clinical question. To date, evidence for TCE in AL amyloidosis is limited to small case series, and their safety—with regard to cytokine release syndrome (CRS), infections, and early organ deterioration in this vulnerable population—remains poorly defined [<span>4-6</span>].</p><p>This retrospective study evaluated all AL amyloidosis patients who received TCE therapy targeting BCMA or GPRC5D between February 2023 and March 2025. Data were collected from nine United States (US) academic centers participating in the US MM Immunotherapy Consortium. Each center obtained Institutional Review Board approval for participation. Dosing followed prescribing information; during step-up, subsequent therapy was at the discretion of the treating physician. Talquetamab was dosed according to the biweekly dosing schedule.</p><p>CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the American Society for Transplantation and Cellular Therapy criteria [<span>7</span>]. Hematologic toxicities were graded according to the Common Terminology Criteria for Adverse Events, v5.0. Infectious disease prophylaxis, use of growth colony-stimulating factor, and treatment of CRS and ICANS were according to institutional guidelines [<span>8</span>]. Hematologic responses were defined according to consensus response criteria [<span>1</span>]. Cardiac and renal responses were defined according to the graded response criteria [<span>9</span>], and cardiac stage per the European modification of the Mayo 2004 model [<span>10</span>]. Data were analyzed using ‘<i>R</i>’ v4.3.2.</p><p>Twenty-nine patients with AL amyloidosis treated with TCEs were included: teclistamab (<i>n</i> = 19), elranatamab (<i>n</i> = 6), and talquetamab (<i>n</i> = 4). Baseline patient, disease and treatment characteristics are summarized in Table 1. The median age was 72 years (IQR: 66–75), with a female predominance (59%). Cardiac stage prior to TCE was known in 26 patients; 2 patients were stage 3A (8%), and 5 patients were stage 3B (19%). Most patients had l","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 1","pages":"187-192"},"PeriodicalIF":9.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70140","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145491636","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}
Megha Verma, Matthew P. Davidsohn, Christopher Maximilian Arends, Divij Verma, Srabani Sahu, Kith Pradhan, Seyedeh Sharareh Dehghani, Hamsa Murli, Sakshi Jasra, Ritesh K. Aggarwal, Hui Zhang, Michael Wysota, Dean Hosgood, Amit Verma, Siddhartha Jaiswal, Yiyu Zou, Aditi Shastri
{"title":"Environmental Pollution Triggers Inflammation In Vivo and is Associated With Higher Risk MDS in an Urban Cohort","authors":"Megha Verma, Matthew P. Davidsohn, Christopher Maximilian Arends, Divij Verma, Srabani Sahu, Kith Pradhan, Seyedeh Sharareh Dehghani, Hamsa Murli, Sakshi Jasra, Ritesh K. Aggarwal, Hui Zhang, Michael Wysota, Dean Hosgood, Amit Verma, Siddhartha Jaiswal, Yiyu Zou, Aditi Shastri","doi":"10.1002/ajh.70132","DOIUrl":"10.1002/ajh.70132","url":null,"abstract":"<p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 2","pages":"346-349"},"PeriodicalIF":9.9,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70132","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485694","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}
{"title":"Efficacy of the VIALE-A Regimen for AML With Monocytic Differentiation as Determined by French-American-British Subtyping and Gene Expression Profiling.","authors":"Shyam A Patel,Jonathan M Gerber","doi":"10.1002/ajh.70136","DOIUrl":"https://doi.org/10.1002/ajh.70136","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"54 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Bakri Hammami, Sean P. Haney, Danny DeAvila, Julia Fadul, Christine E. Simonelli, Samantha C. Seitzler, Sairekha Ravichandran, Melissa Alsina, Brandon Blue, Ariel Grajales-Cruz, Rachid Baz, Kenneth H. Shain
<p>Treatment options for relapsed/refractory multiple myeloma (RRMM) have recently expanded with the approval of bispecific antibodies (BsAbs) [<span>1-4</span>]. These novel agents are engineered to simultaneously engage tumor antigens and immune effector cell receptors, thereby activating T-cell–mediated cytotoxicity against malignant plasma cells [<span>1, 5</span>]. As “off-the-shelf” therapies, BsAbs address key limitations of chimeric antigen receptor (CAR) T-cell therapy, including prolonged manufacturing time, limited accessibility, and a generally more favorable toxicity profile [<span>6</span>]. Currently, the FDA has granted accelerated approval to three BsAb products for patients with RRMM who have received at least four prior lines of therapy: Teclistamab, Elranatamab, and Talquetamab [<span>6</span>]. All three target CD3 on T cells but differ in their tumor-specific targets: Teclistamab and Elranatamab target B-cell maturation antigen (BCMA), while Talquetamab targets GPRC5D (G protein-coupled receptor Family C Group 5 Member D) [<span>7</span>]. These agents have demonstrated high response rates in heavily pretreated patients, including those relapsing after CAR T-cell therapy, highlighting their important role in the management of MM [<span>8</span>].</p><p>Despite their efficacy, BsAbs are associated with a range of toxicities, some class-wide and others antigen-specific [<span>8</span>]. Cytokine release syndrome (CRS) is common across BsAbs, typically occurring during step-up dosing or shortly after the first full dose [<span>5</span>]. Immune effector cell-associated neurotoxicity syndrome (ICANS) has been reported as well, though at a lower incidence (1–14) [<span>5</span>]. Cytopenia and hypogammaglobulinemia are frequently observed, with higher-grade hematologic toxicities more prevalent among BCMA-directed BsAbs [<span>9</span>]. In contrast, target-specific toxicities have also been documented. Most notably, Talquetamab is associated with GPRC5D-related “on target-off tumor” side effects, including (i) taste disturbances and dry mouth, (ii) weight loss, and (iii) dermatologic toxicities such as xerosis, onychomadesis, pruritic maculopapular rash, and palmar/plantar desquamation [<span>8, 10</span>]. These adverse events are attributed to GPRC5D expression in highly keratinized tissue, including hair follicles and nails [<span>10, 11</span>]. BCMA-directed BsAb are more commonly associated with hepatotoxicity, infections, neutropenia, and CRS [<span>12</span>]. Elranatamab, in particular, was associated with dermatologic adverse events in the MagnetisMM-3 trial, though these were limited to injection site reactions (26.8%) [<span>12</span>] Interestingly, we have observed Talquetamab-like dermatologic toxicities in approximately 11% of patients treated with Elranatamab at our institution. To better characterize these toxicities, we present our experience with seven patients who developed dermatologic events while receivin
{"title":"Dermatologic Adverse Effects With Elranatamab Mimicking Talquetamab","authors":"M. Bakri Hammami, Sean P. Haney, Danny DeAvila, Julia Fadul, Christine E. Simonelli, Samantha C. Seitzler, Sairekha Ravichandran, Melissa Alsina, Brandon Blue, Ariel Grajales-Cruz, Rachid Baz, Kenneth H. Shain","doi":"10.1002/ajh.70130","DOIUrl":"10.1002/ajh.70130","url":null,"abstract":"<p>Treatment options for relapsed/refractory multiple myeloma (RRMM) have recently expanded with the approval of bispecific antibodies (BsAbs) [<span>1-4</span>]. These novel agents are engineered to simultaneously engage tumor antigens and immune effector cell receptors, thereby activating T-cell–mediated cytotoxicity against malignant plasma cells [<span>1, 5</span>]. As “off-the-shelf” therapies, BsAbs address key limitations of chimeric antigen receptor (CAR) T-cell therapy, including prolonged manufacturing time, limited accessibility, and a generally more favorable toxicity profile [<span>6</span>]. Currently, the FDA has granted accelerated approval to three BsAb products for patients with RRMM who have received at least four prior lines of therapy: Teclistamab, Elranatamab, and Talquetamab [<span>6</span>]. All three target CD3 on T cells but differ in their tumor-specific targets: Teclistamab and Elranatamab target B-cell maturation antigen (BCMA), while Talquetamab targets GPRC5D (G protein-coupled receptor Family C Group 5 Member D) [<span>7</span>]. These agents have demonstrated high response rates in heavily pretreated patients, including those relapsing after CAR T-cell therapy, highlighting their important role in the management of MM [<span>8</span>].</p><p>Despite their efficacy, BsAbs are associated with a range of toxicities, some class-wide and others antigen-specific [<span>8</span>]. Cytokine release syndrome (CRS) is common across BsAbs, typically occurring during step-up dosing or shortly after the first full dose [<span>5</span>]. Immune effector cell-associated neurotoxicity syndrome (ICANS) has been reported as well, though at a lower incidence (1–14) [<span>5</span>]. Cytopenia and hypogammaglobulinemia are frequently observed, with higher-grade hematologic toxicities more prevalent among BCMA-directed BsAbs [<span>9</span>]. In contrast, target-specific toxicities have also been documented. Most notably, Talquetamab is associated with GPRC5D-related “on target-off tumor” side effects, including (i) taste disturbances and dry mouth, (ii) weight loss, and (iii) dermatologic toxicities such as xerosis, onychomadesis, pruritic maculopapular rash, and palmar/plantar desquamation [<span>8, 10</span>]. These adverse events are attributed to GPRC5D expression in highly keratinized tissue, including hair follicles and nails [<span>10, 11</span>]. BCMA-directed BsAb are more commonly associated with hepatotoxicity, infections, neutropenia, and CRS [<span>12</span>]. Elranatamab, in particular, was associated with dermatologic adverse events in the MagnetisMM-3 trial, though these were limited to injection site reactions (26.8%) [<span>12</span>] Interestingly, we have observed Talquetamab-like dermatologic toxicities in approximately 11% of patients treated with Elranatamab at our institution. To better characterize these toxicities, we present our experience with seven patients who developed dermatologic events while receivin","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 1","pages":"218-221"},"PeriodicalIF":9.9,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70130","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477560","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}
Tzu-Fei Wang, Erik Yeo, Peter L. Gross, Chantal Séguin, Cynthia Wu, Sudeep Shivakumar, Ranjeeta Mallick, Aurélien Delluc, Julien D'Astous, Miriam Kimpton, Guillaume Roberge, Deborah M. Siegal, Tobias Tritschler, Grégoire Le Gal, Marc Carrier
Patients with cancer-associated thrombosis (CAT) are commonly treated with low-molecular-weight heparin (LMWH), but whether dose capping is needed in patients over 90 kg is unclear. We conducted the WAVe study, a multicenter prospective cohort study in adult patients (≥ 18 years) with acute CAT and a weight of over 90 kg starting anticoagulation. Patients received weight-adjusted dalteparin at 200 IU/kg per day (up to 33 000 IU) for 30 (± 4) days, after which anticoagulation was continued per clinician discretion and followed for 6 months. The primary outcome was major bleeding (MB) at 30 days. Secondary outcomes included objectively confirmed recurrent venous thromboembolism (VTE) at 30 days and trough anti-Xa levels. The cumulative incidences of outcomes were estimated by time-to-event analysis, with death as a competing risk. The study stopped early due to recruitment challenges after 91 patients. Median weight and daily dose of dalteparin were 107.5 kg and 22 500 IU, respectively. Three patients had a MB episode for a cumulative incidence of 5.3% (95% CI 1.1%–14.8%) at 30 days. One patient had recurrent VTE for a cumulative incidence of 1.2% (95% CI 0.1%–5.7%) at 30 days. No significant bioaccumulation noted up to Day 30 based on trough anti-Xa levels. The median Day 7 trough anti-Xa levels were higher in those with bleeding events within 30 days compared to those without (0.6 vs. 0.2 IU/mL, p = 0.01). Our results suggest that weight-adjusted dosing of dalteparin in patients over 90 kg is associated with acceptable rates of bleeding and thrombosis.
Trial Registration: NCT03297359
癌症相关性血栓（CAT）患者通常使用低分子肝素（LMWH）治疗，但对于体重超过90公斤的患者是否需要剂量上限尚不清楚。我们进行了WAVe研究，这是一项多中心前瞻性队列研究，研究对象是患有急性CAT且体重超过90kg开始抗凝治疗的成年患者（≥18岁）。患者接受体重调整后的达特帕林治疗，剂量为每天200 IU/kg（最高33,000 IU），持续30（±4）天，之后根据临床医生的判断继续抗凝治疗，随访6个月。主要结局为30天大出血（MB）。次要结果包括客观确认的30天静脉血栓栓塞复发（VTE）和抗xa水平谷底。结果的累积发生率通过事件时间分析估计，死亡是一个竞争风险。由于91名患者的招募挑战，该研究提前停止。dalteparin的中位体重和日剂量分别为107.5 kg和22 500 IU。3例患者在30天发生MB发作，累计发生率为5.3% （95% CI 1.1%-14.8%）。1例患者30天静脉血栓栓塞复发，累计发生率为1.2% （95% CI 0.1%-5.7%）。根据抗xa谷底水平，在第30天没有发现显著的生物积累。30天内有出血事件的患者第7天抗xa水平中位数高于无出血事件的患者（0.6 vs. 0.2 IU/mL, p = 0.01）。我们的研究结果表明，体重超过90公斤的患者的体重调整剂量与可接受的出血和血栓发生率相关。试验注册：NCT03297359。
{"title":"A Multicenter Prospective Cohort Study on the Use of Weight-Adjusted Dalteparin in Patients Over 90 kg With Acute Cancer-Associated Venous Thromboembolism—The WAVe Study","authors":"Tzu-Fei Wang, Erik Yeo, Peter L. Gross, Chantal Séguin, Cynthia Wu, Sudeep Shivakumar, Ranjeeta Mallick, Aurélien Delluc, Julien D'Astous, Miriam Kimpton, Guillaume Roberge, Deborah M. Siegal, Tobias Tritschler, Grégoire Le Gal, Marc Carrier","doi":"10.1002/ajh.70127","DOIUrl":"10.1002/ajh.70127","url":null,"abstract":"<p>Patients with cancer-associated thrombosis (CAT) are commonly treated with low-molecular-weight heparin (LMWH), but whether dose capping is needed in patients over 90 kg is unclear. We conducted the WAVe study, a multicenter prospective cohort study in adult patients (≥ 18 years) with acute CAT and a weight of over 90 kg starting anticoagulation. Patients received weight-adjusted dalteparin at 200 IU/kg per day (up to 33 000 IU) for 30 (± 4) days, after which anticoagulation was continued per clinician discretion and followed for 6 months. The primary outcome was major bleeding (MB) at 30 days. Secondary outcomes included objectively confirmed recurrent venous thromboembolism (VTE) at 30 days and trough anti-Xa levels. The cumulative incidences of outcomes were estimated by time-to-event analysis, with death as a competing risk. The study stopped early due to recruitment challenges after 91 patients. Median weight and daily dose of dalteparin were 107.5 kg and 22 500 IU, respectively. Three patients had a MB episode for a cumulative incidence of 5.3% (95% CI 1.1%–14.8%) at 30 days. One patient had recurrent VTE for a cumulative incidence of 1.2% (95% CI 0.1%–5.7%) at 30 days. No significant bioaccumulation noted up to Day 30 based on trough anti-Xa levels. The median Day 7 trough anti-Xa levels were higher in those with bleeding events within 30 days compared to those without (0.6 vs. 0.2 IU/mL, <i>p</i> = 0.01). Our results suggest that weight-adjusted dosing of dalteparin in patients over 90 kg is associated with acceptable rates of bleeding and thrombosis.</p><p>\u0000 <b>Trial Registration:</b> NCT03297359</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 1","pages":"79-88"},"PeriodicalIF":9.9,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70127","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477557","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}
Francesco Pegoraro, Francesco Peyronel, Matthias Papo, Riccardo Sutera, Francesco Catamerò, Francesco Poeta, Jerome Razanamahery, Emmanuel Ledoult, Tanguy Le Scornet, Mathilde de Menthon, Etienne Riviere, Elena Sieni, Stephane Barete, Ahmed Idbaih, Fleur Cohen-Aubart, Zahir Amoura, Jean-François Emile, Augusto Vaglio, Julien Haroche
<p>Erdheim-Chester disease (ECD) is a rare myeloid neoplasm driven by somatic mutations in genes of the MAPK pathway [<span>1</span>]. The <i>BRAF</i> <sup> <i>V600E</i> </sup> mutation is found in ~60% of ECD patients and can be targeted by specific inhibitors (BRAFi), such as vemurafenib, dabrafenib, and encorafenib [<span>1</span>]. The introduction in 2013 of BRAFi—and more recently of MEK inhibitors (MEKi)—revolutionized the management of patients with ECD [<span>2-4</span>]. These treatments induce rapid and sustained responses, but relapses occur in most cases upon discontinuation, which is usually prompted by their toxicity [<span>2</span>].</p><p>In a recent report on 64 ECD patients treated with BRAFi, discontinuations were very frequent (61%) and mostly induced by adverse events, with poor health-related quality of life and high symptom burden [<span>5</span>]. In contrast, our routine clinical experience suggests a more favorable tolerability profile, with fewer discontinuations and generally manageable toxicities. We herein investigated the real-life efficacy and tolerability of BRAFi monotherapy in a large cohort of patients with ECD.</p><p>Patients were diagnosed according to the latest consensus guidelines on ECD [<span>6</span>], and followed in France (Pitié-Salpêtrière Hospital, Paris; Dijon University Hospital, Dijon; Lille University Hospital, Lille; Nantes University Hospital, Nantes; Bicêtre Hospital, Le Kremlin Bicêtre; Haut-Lévèque University Hospital, Bordeaux) and Italy (Meyer Children's Hospital IRCCS, Florence).</p><p>We assessed response to treatment, tolerability (according to the CTCAE criteria) [<span>7</span>], and potential predictors of response. Response was defined as a composite endpoint including clinical, radiologic, and metabolic features, as previously described [<span>8-10</span>]. The event-free survival was defined as the time to treatment discontinuation due to progression or toxicity, or death, and was estimated using a Kaplan–Meier survival analysis. Dose modifications were not considered events. Predictors of response to BRAFi were investigated through univariable and multivariable logistic regression models. A two-sided <i>p</i> value ≤ 0.05 was considered to indicate statistical significance. The study was approved by the Ethics committee of the Ile de France III (#2011-A00447-34) and the Institutional Review Board of the Meyer Children's Hospital IRCCS (#139/2020) and was conducted in accordance with the Declaration of Helsinki and its later amendments [<span>11</span>].</p><p>We identified 172 patients with ECD, all harboring the <i>BRAF</i> <sup> <i>V600E</i> </sup> mutation, who received BRAFi monotherapy since 2012 (Figure 1A). The clinical presentation is detailed in Table 1. Their median age at ECD diagnosis was 59 years (IQR 49–69), and 119 were men (69%). A hundred and twenty-nine patients (75%) had mult
{"title":"Real-Life Efficacy and Safety of BRAF Inhibitors in Erdheim-Chester Disease","authors":"Francesco Pegoraro, Francesco Peyronel, Matthias Papo, Riccardo Sutera, Francesco Catamerò, Francesco Poeta, Jerome Razanamahery, Emmanuel Ledoult, Tanguy Le Scornet, Mathilde de Menthon, Etienne Riviere, Elena Sieni, Stephane Barete, Ahmed Idbaih, Fleur Cohen-Aubart, Zahir Amoura, Jean-François Emile, Augusto Vaglio, Julien Haroche","doi":"10.1002/ajh.70137","DOIUrl":"10.1002/ajh.70137","url":null,"abstract":"<p>Erdheim-Chester disease (ECD) is a rare myeloid neoplasm driven by somatic mutations in genes of the MAPK pathway [<span>1</span>]. The <i>BRAF</i>\u0000 <sup>\u0000 <i>V600E</i>\u0000 </sup> mutation is found in ~60% of ECD patients and can be targeted by specific inhibitors (BRAFi), such as vemurafenib, dabrafenib, and encorafenib [<span>1</span>]. The introduction in 2013 of BRAFi—and more recently of MEK inhibitors (MEKi)—revolutionized the management of patients with ECD [<span>2-4</span>]. These treatments induce rapid and sustained responses, but relapses occur in most cases upon discontinuation, which is usually prompted by their toxicity [<span>2</span>].</p><p>In a recent report on 64 ECD patients treated with BRAFi, discontinuations were very frequent (61%) and mostly induced by adverse events, with poor health-related quality of life and high symptom burden [<span>5</span>]. In contrast, our routine clinical experience suggests a more favorable tolerability profile, with fewer discontinuations and generally manageable toxicities. We herein investigated the real-life efficacy and tolerability of BRAFi monotherapy in a large cohort of patients with ECD.</p><p>Patients were diagnosed according to the latest consensus guidelines on ECD [<span>6</span>], and followed in France (Pitié-Salpêtrière Hospital, Paris; Dijon University Hospital, Dijon; Lille University Hospital, Lille; Nantes University Hospital, Nantes; Bicêtre Hospital, Le Kremlin Bicêtre; Haut-Lévèque University Hospital, Bordeaux) and Italy (Meyer Children's Hospital IRCCS, Florence).</p><p>We assessed response to treatment, tolerability (according to the CTCAE criteria) [<span>7</span>], and potential predictors of response. Response was defined as a composite endpoint including clinical, radiologic, and metabolic features, as previously described [<span>8-10</span>]. The event-free survival was defined as the time to treatment discontinuation due to progression or toxicity, or death, and was estimated using a Kaplan–Meier survival analysis. Dose modifications were not considered events. Predictors of response to BRAFi were investigated through univariable and multivariable logistic regression models. A two-sided <i>p</i> value ≤ 0.05 was considered to indicate statistical significance. The study was approved by the Ethics committee of the Ile de France III (#2011-A00447-34) and the Institutional Review Board of the Meyer Children's Hospital IRCCS (#139/2020) and was conducted in accordance with the Declaration of Helsinki and its later amendments [<span>11</span>].</p><p>We identified 172 patients with ECD, all harboring the <i>BRAF</i>\u0000 <sup>\u0000 <i>V600E</i>\u0000 </sup> mutation, who received BRAFi monotherapy since 2012 (Figure 1A). The clinical presentation is detailed in Table 1. Their median age at ECD diagnosis was 59 years (IQR 49–69), and 119 were men (69%). A hundred and twenty-nine patients (75%) had mult","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 1","pages":"182-186"},"PeriodicalIF":9.9,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.70137","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145461314","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}
Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable clinical efficacy in treating hematological malignancies. Nevertheless, the limited persistence of CAR-T cells in vivo remains a major therapeutic hurdle, leading to disease relapse. This review examines current strategies to enhance CAR-T cell durability, focusing on recent advances in CAR structural design, gene editing techniques, ex vivo culture optimization, clinical management approaches, and in vivo preparation. By integrating insights from preclinical studies and clinical trials, we provide a comprehensive analysis of methods to prolong CAR-T cell persistence from a technical perspective and discuss future directions.
{"title":"Strategies to Enhance CAR-T Cell Persistence in Hematologic Malignancies: From Molecular Design to Clinical Optimization","authors":"Mengqi Yu, Tingting Yang, Shuyi Ding, Yongxian Hu","doi":"10.1002/ajh.70131","DOIUrl":"10.1002/ajh.70131","url":null,"abstract":"<div>\u0000 \u0000 <p>Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable clinical efficacy in treating hematological malignancies. Nevertheless, the limited persistence of CAR-T cells in vivo remains a major therapeutic hurdle, leading to disease relapse. This review examines current strategies to enhance CAR-T cell durability, focusing on recent advances in CAR structural design, gene editing techniques, ex vivo culture optimization, clinical management approaches, and in vivo preparation. By integrating insights from preclinical studies and clinical trials, we provide a comprehensive analysis of methods to prolong CAR-T cell persistence from a technical perspective and discuss future directions.</p>\u0000 </div>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 2","pages":"318-336"},"PeriodicalIF":9.9,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145461402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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