American Journal of Hematology最新文献_第10页

Mitapivat for phosphofructokinase deficiency Mitapivat 用于治疗磷酸果糖激酶缺乏症。

IF 10.1 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2024-07-23 DOI: 10.1002/ajh.27442

Hanny Al-Samkari

Pyruvate kinase activation is an emerging therapeutic modality under evaluation to treat congenital hemolytic anemias, including pyruvate kinase deficiency, thalassemia, and sickle cell disease, among others.1, 2 The results of a phase 3, randomized, placebo-controlled clinical trial of the pyruvate kinase activator mitapivat to treat the most common glycolytic enzyme defect, pyruvate kinase deficiency, were previously published.1 Because mitapivat increases glycolytic flux via allosteric activation of multiple isoforms of pyruvate kinase, it may provide therapeutic benefit in other glycolytic disorders, particularly those resulting in pathologic accumulation of glycolytic intermediates. Phosphofructokinase, another critical glycolytic enzyme, catalyzes the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Phosphofructokinase deficiency (glycogen storage disease type VII, Tarui disease), an ultrarare enzymopathy occurring in fewer than 1 in 1 000 000 people, causes accumulation of fructose-6-phosphate which is ultimately converted to glycogen that builds up in muscle tissue, resulting in easy fatigability, muscle weakness and pain, myoglobinuria, rhabdomyolysis, and hemolysis.3 Phosphofructokinase deficiency has no known effective treatments. The safety and effectiveness of mitapivat in a patient with phosphofructokinase deficiency are described herein.A 29-year-old man with classic phosphofructokinase deficiency presenting with lifelong easy fatigability, muscle weakness and pain, and hemolysis (without anemia) resulting in severe physical activity limitation and poor health-related quality of life was treated with oral mitapivat with close monitoring for safety and effectiveness. The patient's diagnosis was confirmed via genetic testing demonstrating two known pathogenic mutations in the M isoform of phosphofructokinase (PFKM c.2003delC [p.Pro668Glnfs*17] and PFKM c.237+1G>A [splice donor variant]). At baseline, the patient scored poorly across all eight domains of the well-validated Short Form-36 Health Survey (SF-36), but dose-dependent and ultimately marked improvements across all eight domains were observed with mitapivat treatment (Figure 1). Mitapivat was well-tolerated with no adverse events except mild transient erythrocytosis (hematocrit 61%, up from pretreatment baseline of 46%) after initial dose escalation to 20 mg twice daily; this resolved with a temporary dose decrease to 20 mg once daily and did not recur following resumption of 20 mg twice daily or dose escalation to 50 mg once daily. While the maximum approved mitapivat dose for pyruvate kinase deficiency is 50 mg twice daily, the decision was made to stay at 50 mg daily and not dose escalate to 50 mg twice daily because the patient felt markedly improved on 50 mg once daily and there was a desire to avoid potential recurrence of erythrocytosis.Consistent wi

米他匹伐治疗磷酸果糖激酶缺乏症属于标签外使用。

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引用次数: 0

Network meta-analysis of upfront fixed-duration therapies in chronic lymphocytic leukemia 慢性淋巴细胞白血病前期固定疗程疗法的网络荟萃分析。

IF 10.1 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2024-07-23 DOI: 10.1002/ajh.27437

Stefano Molica, David Allsup, Diana Giannarelli

The emergence of Bruton's tyrosine kinase (BTK) inhibitors marked a significant advancement in chronic lymphocytic leukemia (CLL) management, especially for high-risk patients.1 Ibrutinib, the pioneering BTK inhibitor, has undergone extensive study. The final analysis of the RESONATE-2 study confirms its sustained survival benefit for first-line CLL treatment with up to 10 years of follow-up.2 Despite its efficacy, prolonged administration of BTK inhibitors can lead to cardiovascular toxicities and emergence of therapy resistance mutations.3, 4Time-limited CLL-directed therapies, inspired by venetoclax's unique attributes in inducing deep therapeutic responses, aim to address continuous therapy limitations.5 Venetoclax combined with anti-CD20 monoclonal antibodies in fixed-duration (FD) regimens, showcased in relapsed/refractory CLL with MURANO and in frontline with CLL14 and CLL13 trials, sustain responses with manageable toxicity across CLL patient profiles.6-9By harnessing the synergistic potential of venetoclax and ibrutinib (VI), which combines agents with distinct mechanisms of action and non-overlapping toxicities, researchers aim to attain deeper and persistent treatment responses without associated therapy resistance.10-14 This combination has recently received approval from the European Medicines Agency (EMA) for frontline treatment of CLL.15 This approval is based on pivotal findings from the Phase 3 GLOW study, which demonstrated superior PFS in patients treated with VI compared with those treated with chlorambucil-obinutuzumab, and from the FD cohort of the Phase 2 CAPTIVATE study.10, 11 However, the choice between FD therapies remains challenging due to the lack of head-to-head comparative data. Results from the ongoing CLL17 trial (NCT04608318), which is comparing continuous BTK inhibitor therapy with FD regimens, including VI and venetoclax-obinutuzumab (VO), are eagerly anticipated.To provisionally support evidence-based decision-making, we performed a network meta-analysis (NMA) comparing all approved FD therapies in the setting of treatment-naïve (TN) CLL patients.Relevant randomized clinical trials were identified through a systematic review of the literature in MEDLINE. To be included, studies had to meet the following criteria: (1) to be randomized controlled trials (RCTs) focusing on FD therapy in TN CLL patients; (2) to investigate the effectiveness of FD therapy with venetoclax as its core component; and (3) to provide data on both progression-free survival (PFS) and overall survival (OS). Reporting of the systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.16 Two reviewers (S.M. and D.G.) independently assessed

布鲁顿酪氨酸激酶（BTK）抑制剂的出现标志着慢性淋巴细胞白血病（CLL）治疗的重大进展，尤其是对高危患者的治疗。RESONATE-2研究的最终分析证实，在长达10年的随访中，伊布替尼对CLL一线治疗具有持续的生存获益。2 尽管BTK抑制剂疗效显著，但长期用药会导致心血管毒性和耐药突变的出现、5 Venetoclax 与抗 CD20 单克隆抗体联合应用于固定持续时间（FD）疗法，在复发/难治性 CLL 的 MURANO 试验以及前线 CLL14 和 CLL13 试验中均得到了展示，可在 CLL 患者中维持反应并控制毒性。通过利用 Venetoclax 和 ibrutinib (VI) 的协同潜力（这两种药物具有不同的作用机制和不重叠的毒性），研究人员旨在获得更深入和持久的治疗反应，同时避免出现相关的耐药性。这一批准是基于 3 期 GLOW 研究的关键性结果（该研究显示，与氯丁珠单抗-奥比妥珠单抗治疗相比，VI 治疗患者的 PFS 更优）以及 2 期 CAPTIVATE 研究的 FD 队列。目前正在进行的 CLL17 试验（NCT04608318）比较了连续 BTK 抑制剂疗法和 FD 方案（包括 VI 和 Venetoclax-obinutuzumab，VO），其结果令人期待。为了给循证决策提供临时支持，我们进行了一项网络荟萃分析（NMA），比较了所有获批的 FD 疗法在治疗无效（TN）CLL 患者中的应用。纳入的研究必须符合以下标准：(1)随机对照试验（RCT）侧重于 TN CLL 患者的 FD 治疗；(2)研究以 venetoclax 为核心成分的 FD 治疗的有效性；(3)提供无进展生存期（PFS）和总生存期（OS）的数据。系统综述的报告遵循《系统综述和荟萃分析首选报告项目》（Preferred Reporting Items for Systematic Reviews and Meta-Analyses，PRISMA）指南16。两名审稿人（S.M.和D.G.）独立评估了所有已识别引文的资格，并从原始试验报告中提取了数据。在随机效应 NMA 中提取并综合了一致的疗效终点，如 PFS 和 OS。采用推荐、评估、发展和评价分级（GRADE）工作组17 制定的推荐策略（补充材料），对数据充足的所有结果的证据质量和确定性进行了评估。采用图解法显示直接和间接比较的危险比（HR）值，以直观的方式综合实验证据。如果HR的95%置信区间(CI)不包括1.0的值（对应于贝叶斯概率p≥97.5%），则认为一种治疗方法比另一种治疗方法更有效：CLL14，76.4 个月；GLOW，57 个月；FLAIR，43.7 个月；CLL13，50.7 个月。CLL13和FLAIR招募了较年轻、体质较好的患者，而CLL14和GLOW招募了较年长、体质较差的患者。造成这种异质性的主要原因是，与 GLOW 试验相比，CLL14 试验中累积疾病评分量表 (CIRS) 得分超过 6 分的患者比例更高（p = 0.0004）。此外，与FLAIR试验相比，CLL13试验中免疫球蛋白重链可变区（IGHV）基因未突变患者的发病率更高（p = .03）（补充表1）。试验分析组由1632名患者组成，其中819人（50.1%）接受靶向药物的FD治疗，813人（49.8%）接受化学免疫疗法（CIT）。靶向药物治疗组对 366 例（44.8%）患者进行了 VI 联合疗法评估。

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引用次数: 0

Advances in sickle cell retinopathy screening techniques, tests, and practices: A systematic review 镰状细胞视网膜病变筛查技术、测试和实践的进展：系统综述。

IF 10.1 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2024-07-23 DOI: 10.1002/ajh.27439

Olivia W. Cummings, Sara Rahman, Lauren Fletcher, Adrienne W. Scott

Sickle cell retinopathy (SCR) is a progressive, sight-threatening ophthalmic complication of sickle cell disease (SCD). Current SCR screening focuses on the detection of pathologic sea fan neovascularization, the first sign of proliferative sickle cell retinopathy (PSR). If untreated, PSR can lead to severe visual impairment and blindness through progression to vitreous hemorrhage and/or retinal detachment. SCR screening with dilated fundus examination (DFE) is recommended every 1–2 years starting at age 10, but data underlying this recommendation are of poor quality and based upon expert consensus. We performed a systematic review to characterize imaging techniques, laboratory-based tests, and clinical practices for SCR screening. This PROSPERO-registered systematic review included relevant texts identified through predetermined searches in online databases. Collected test accuracy data facilitated the calculation of likelihood ratios. Forty-four studies evaluating 4928 patients were included. DFE demonstrated moderate test accuracy (LR+ of 8.0, LR- of 0.3). Ultra-widefield-fundus photography demonstrated superior accuracy (LR+ 32.5, LR- 0.03). Optical coherence tomography angiography applications were highly accurate for PSR identification (machine learning LR+ 32.5, LR- 0.03; human grader LR+ 2.8–213.1, LR- 0.1-0.2). Most techniques and tests were more accurate at detecting PSR than staging SCR or detecting lower-grade SCR. Our findings support the integration of advanced image-based approaches, such as computer-based image analysis and ultra-wide-field fundus imaging, for SCR screening in SCD patients given the superior accuracy in PSR detection compared with the current standard of care. Rigorous SCR screening implementation studies are needed to support evidence-based SCR screening recommendations.

镰状细胞视网膜病变（SCR）是镰状细胞病（SCD）的一种渐进性、危及视力的眼科并发症。目前的镰状细胞视网膜病变筛查主要是检测病理性海扇状新生血管，这是增殖性镰状细胞视网膜病变（PSR）的第一个征兆。如果不及时治疗，增殖性镰状细胞视网膜病变会发展为玻璃体出血和/或视网膜脱离，从而导致严重的视力损伤和失明。建议从 10 岁开始每隔 1-2 年通过散瞳眼底检查（DFE）进行 SCR 筛查，但该建议所依据的数据质量不高，而且是基于专家共识。我们对 SCR 筛查的成像技术、实验室测试和临床实践进行了系统回顾。这项已在 PROSPERO 注册的系统性综述包括了通过在线数据库的预定搜索而确定的相关文本。收集的检验准确性数据有助于计算似然比。共纳入了 44 项研究，对 4928 名患者进行了评估。DFE显示了中等程度的测试准确性（LR+为8.0，LR-为0.3）。超宽场-丰度摄影显示出更高的准确性（LR+ 32.5，LR- 0.03）。光学相干断层血管造影应用在 PSR 识别方面的准确率很高（机器学习 LR+ 32.5，LR- 0.03；人工分级 LR+ 2.8-213.1，LR- 0.1-0.2）。与分期 SCR 或检测低级别 SCR 相比，大多数技术和测试在检测 PSR 方面更为准确。我们的研究结果支持将先进的基于图像的方法（如基于计算机的图像分析和超宽视野眼底成像）整合到 SCD 患者的 SCR 筛查中，因为 PSR 检测的准确性优于当前的护理标准。需要开展严格的 SCR 筛查实施研究，以支持循证 SCR 筛查建议。

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引用次数: 0

Disease burden, management strategies, and unmet needs in α-thalassemia due to hemoglobin H disease 血红蛋白 H 病导致的 α 地中海贫血症的疾病负担、管理策略和未满足的需求。

IF 10.1 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2024-07-22 DOI: 10.1002/ajh.27440

Ashutosh Lal, Vip Viprakasit, Elliott Vichinsky, Yongrong Lai, Meng-Yao Lu, Antonis Kattamis

Alpha-thalassemia is an inherited blood disorder caused by impaired α-globin chain production, leading to anemia and other complications. Hemoglobin H (HbH) disease is caused by a combination of mutations generally affecting the expression of three of four α-globin alleles; disease severity is highly heterogeneous, largely driven by genotype. Notably, non-deletional mutations cause a greater degree of ineffective erythropoiesis and hemolysis, higher transfusion burden, and increased complication risks versus deletional mutations. There are limited treatment options for HbH disease, and effective therapies are needed. This review discusses the pathophysiology of HbH disease, current management strategies, unmet needs, and emerging treatment options.

α-地中海贫血症是一种遗传性血液疾病，由α-球蛋白链生成障碍引起，会导致贫血和其他并发症。血红蛋白 H（HbH）病是由多种突变引起的，通常影响四种 α-球蛋白等位基因中三种等位基因的表达；疾病的严重程度差异很大，主要取决于基因型。值得注意的是，与缺失性突变相比，非缺失性突变会导致更严重的无效红细胞生成和溶血、更高的输血负担以及更高的并发症风险。目前治疗 HbH 病的方法有限，需要有效的疗法。本综述将讨论 HbH 病的病理生理学、当前的治疗策略、未满足的需求以及新出现的治疗方案。

引用次数: 0

Risk of myeloproliferative neoplasms among U.S. Veterans from Korean, Vietnam, and Persian Gulf War eras 朝鲜战争、越南战争和波斯湾战争时期美国退伍军人患骨髓增生性肿瘤的风险。

IF 10.1 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2024-07-18 DOI: 10.1002/ajh.27438

Andrew Tiu, Zoe McKinnell, Shanshan Liu, Puneet Gill, Martha Antonio, Zoe Shancer, Nandan Srinivasa, Guoqing Diao, Ramesh Subrahmanyam, Craig M. Kessler, Maneesh Jain

The Promise to Address Comprehensive Toxics (PACT) Act expanded U.S. Veterans' health care and benefits for conditions linked to service-connected exposures (e.g., Burn Pits, Agent Orange). However, myeloproliferative neoplasms (MPN) are not recognized as presumptive conditions for Veterans exposed to these toxic substances. This study evaluated the development of MPN among U.S. Veterans from the Korean, Vietnam, and Persian Gulf War eras. This retrospective cohort study included 65 425 Korean War era Veterans; 211 927 Vietnam War era Veterans; and 214 007 Persian Gulf War era Veterans from January 1, 2006, to January 26, 2023. Veterans with MPN, thrombosis, bleeding, and cardiovascular risk factors were identified through ICD-9 and -10 codes. Veterans from the Persian Gulf War era had the highest risk of developing MPN compared with Veterans from the Korean and Vietnam War eras, hazard ratio (HR) 4.92, 95% confidence interval (CI) 4.20–5.75 and HR 2.49, 95% CI 2.20–2.82, both p < .0001, respectively. Vietnam War era Veterans also had a higher risk of MPN development compared with Korean War era Veterans, HR 1.97, 95% CI 1.77–2.21, p < .0001. Persian Gulf War era Veterans were diagnosed with MPN at an earlier age, had higher risks of thrombosis and bleeding, and had lower survival rates compared with Korean War and Vietnam War era Veterans. This study reinforces evidence that environmental and occupational hazards increase the risk of clonal myeloid disorders and related complications, impacting overall survival with MPN. Limitations include the inability to confirm clonality and fully verify deployment and exposure status.

承诺解决全面有毒物质 (PACT) 法案》扩大了美国退伍军人的医疗保健范围，并针对与服役有关的暴露（如烧伤坑、橙剂）相关的病症提供福利。然而，骨髓增生性肿瘤 (MPN) 并未被确认为退伍军人接触这些有毒物质的推定病症。本研究评估了朝鲜战争、越南战争和波斯湾战争时期美国退伍军人中 MPN 的发病情况。这项回顾性队列研究纳入了 65 425 名朝鲜战争时期的退伍军人、211 927 名越南战争时期的退伍军人和 214 007 名波斯湾战争时期的退伍军人，研究时间为 2006 年 1 月 1 日至 2023 年 1 月 26 日。通过 ICD-9 和 -10 编码确定退伍军人是否患有多发性骨髓瘤、血栓、出血和心血管风险因素。与朝鲜战争和越南战争时期的退伍军人相比，波斯湾战争时期的退伍军人罹患 MPN 的风险最高，危险比 (HR) 为 4.92，95% 置信区间 (CI) 为 4.20-5.75 和 HR 为 2.49，95% 置信区间 (CI) 为 2.20-2.82，均为 p。

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引用次数: 0

A growing panoply of options for patients with paroxysmal nocturnal hemoglobinuria 阵发性夜间血红蛋白尿患者的选择越来越多。

IF 10.1 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2024-07-18 DOI: 10.1002/ajh.27426

David J. Young

In this issue, the COMMODORE 11 and COMMODORE 22 trials of crovalimab for previously treated and treatment-naïve paroxysmal nocturnal hemoglobinuria, respectively, are presented, demonstrating efficacy and safety for both patient populations in comparison with the benchmark, eculizumab.Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic anemia characterized by sometimes painful intravascular hemolysis (IVH), pancytopenia with increased infections, and significant risk of potentially fatal venous thrombosis especially of the sagittal sinuses and hepatoportal system. Instead of autoantibodies, PNH is a clonal disorder driven by the acquisition of somatic mutations in PIGA. These mutations, as well as rarer mutations in related genes, lead to loss of the glycosylphosphatidylinositol (GPI) anchor required for presenting an array of cell-surface proteins. Loss of GPI anchorage has wide ranging consequences, key among them is loss of CD55 and CD59, proteins essential for regulating cell surface-aspects of complement (Figure 1). Without CD55 and CD59, complement complexes cannot be removed from the cell surface, leading to C5 activation, membrane attack complex (MAC) formation, and cell lysis. This causes erythrocyte destruction, thrombosis through inappropriate platelet activation, and infections secondary to leukopenia. As the PIGA-deficient clone or clones expand—patients often acquire multiple, separate mutations—the risk and severity of these complications increase. The causes and mechanisms underlying this expansion are complex and beyond the scope of this commentary.3-5Historically, non-transplant management of PNH consisted of anticoagulation—typically anti-vitamin K—and supportive care. However, lifelong anticoagulation has obvious hemorrhagic risks and does not address ongoing hemolysis. Recognition that the clinical manifestations of PNH arise from inappropriate complement-mediated cell membrane attack led to the development of the terminal complement inhibitor eculizumab. By targeting C5, the key enzyme downstream of all complement pathways, eculizumab prevents the final step in cell lysis: membrane disruption by MAC (Figure 1). Provided as fortnightly intravenous infusions, eculizumab has proven revolutionary in the treatment of PNH, eliminating anemia and transfusion requirements for 49% of subjects in the TRIUMPH study6 (increasing to 88% in long-term follow-up7) and reducing the risks of thrombosis and its recurrence by 85%.8 It received FDA approval as the first PNH-specific treatment in 2007. As such, it has become the gold standard against which novel treatments are assessed.Crovalimab is a humanized anti-C5 monoclonal antibody engineered to be recycled instead of cleared following Fcγ receptor binding, leading to a prolonged half-life and the ability

本期将介绍分别针对既往治疗过的阵发性夜间血红蛋白尿症和治疗无效的阵发性夜间血红蛋白尿症进行的 crovalimab 试验 COMMODORE 11 和 COMMODORE 22，与基准药物 eculizumab 相比，这两项试验均证明了这两种患者的疗效和安全性。阵发性夜间血红蛋白尿（PNH）是一种溶血性贫血，其特点是有时会出现痛苦的血管内溶血（IVH），泛发性血小板减少并伴有感染增加，潜在致命的静脉血栓风险很大，尤其是矢状窦和肝门系统。与自身抗体不同，PNH 是一种由 PIGA 体细胞突变引起的克隆性疾病。这些突变以及相关基因的罕见突变会导致呈现一系列细胞表面蛋白所需的糖基磷脂酰肌醇（GPI）锚的缺失。GPI 锚定的缺失会产生广泛的后果，其中最主要的是 CD55 和 CD59 的缺失，它们是调节细胞表面补体的重要蛋白质（图 1）。没有 CD55 和 CD59，补体复合物就无法从细胞表面移除，从而导致 C5 激活、膜攻击复合物（MAC）形成和细胞裂解。这将导致红细胞破坏、血小板不适当活化导致血栓形成以及继发于白细胞减少症的感染。随着 PIGA 缺陷克隆的扩大（患者通常会获得多个独立的突变），这些并发症的风险和严重程度也会增加。这种扩增的原因和机制非常复杂，超出了本评论的范围。3-5 历史上，PNH 的非移植治疗包括抗凝（通常是抗维生素 K）和支持性护理。然而，终生抗凝具有明显的出血风险，而且无法解决持续溶血问题。人们认识到，PNH 的临床表现源于不适当的补体介导的细胞膜攻击，因此开发出了末端补体抑制剂 eculizumab。通过靶向所有补体途径下游的关键酶 C5，eculizumab 可阻止细胞溶解的最后一步：MAC 破坏细胞膜（图 1）。在 TRIUMPH 研究6 中，49% 的受试者不再需要贫血和输血（在长期随访中，这一比例上升到 88%7），血栓形成及其复发的风险降低了 85%8 。Crovalimab 是一种人源化的抗 C5 单克隆抗体，在与 Fcγ 受体结合后会被回收而不是清除，从而延长了半衰期，并能通过皮下注射给药。COMPOSER 1/2期试验证明了该药对PNH的安全性和潜在疗效，随后又进行了两项3期（COMMODORE）试验，本期将介绍试验结果。COMMODORE 1 试验将 crovalimab 作为一种替代治疗方法，用于既往接受过 eculizumab 治疗的成年 PNH 患者。受试者被随机分配到继续维持依库珠单抗或在初始负荷剂量后每 4 周注射一次 crovalimab，持续 24 周。初治期结束后，所有受试者均可继续接受或交叉接受卡瓦单抗治疗。两组患者的CH50均有所下降。使用巴伐利单抗的受试者的C5水平比研究前的维持水平进一步降低（从基线的0.3克/升降至0.18克/升，而使用依库珠单抗的整个疗程为0.28克/升）。临床上，92.9%的受试者在使用巴伐利单抗后溶血得到控制，而使用依库珠单抗的受试者为93.7%。COMMODORE 2同样考察了巴伐利单抗作为PNH一线治疗（补体抑制新药）的安全性和有效性。患者接受了与 COMMODORE 1 相同的随机分组和治疗方案，包括交叉使用巴伐利单抗的可选延期治疗。在治疗无效的患者中，就溶血控制（79.3%对依库珠单抗的79.0%）、LDH正常化和避免输血（65.7%对68.1%）而言，巴伐利单抗并不优于依库珠单抗。BTH率（10.4%对14.5%）和血红蛋白稳定率（63.4%对60.9%）相似。COMMODORE 2 的应答率略低，这几乎可以肯定是由于招募了治疗无效患者而非先前接受过治疗的患者。注射部位反应并不常见（COMMODORE 1：9.1%；COMMODORE 2：5.2%），属于轻度至中度反应，无需调整剂量。初始负荷剂量期间发生输注相关反应的频率与依库珠单抗相似（COMMODORE 1：13.6%；COMMODORE 2：15.6%，依库珠单抗为 13.0%）。

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引用次数: 0

Optical genome mapping improves the accuracy of classification, risk stratification, and personalized treatment strategies for patients with acute myeloid leukemia 光学基因组图谱提高了急性髓性白血病患者的分类、风险分层和个性化治疗策略的准确性。

IF 10.1 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2024-07-17 DOI: 10.1002/ajh.27435

Sanam Loghavi, Qing Wei, Farhad Ravandi, Andres E. Quesada, Mark J. Routbort, Shimin Hu, Gokce A. Toruner, Sa A. Wang, Wei Wang, Roberto N. Miranda, Shaoying Li, Jie Xu, Courtney D. DiNardo, Naval Daver, Tapan M. Kadia, Ghayas C. Issa, Hagop M. Kantarjian, L. Jeffrey Medeiros, Guilin Tang

Cytogenomic characterization is crucial for the classification and risk stratification of acute myeloid leukemia (AML), thereby facilitating therapeutic decision-making. We examined the clinical utility of optical genome mapping (OGM) in 159 AML patients (103 newly diagnosed and 56 refractory/relapsed), all of whom also underwent chromosomal banding analysis (CBA), fluorescence in situ hybridization, and targeted next-generation sequencing. OGM detected nearly all clinically relevant cytogenetic abnormalities that SCG identified with >99% sensitivity, provided the clonal burden was above 20%. OGM identified additional cytogenomic aberrations and/or provided information on fusion genes in 77 (48%) patients, including eight patients with normal karyotypes and four with failed karyotyping. The most common additional alterations identified by OGM included chromoanagenesis (n = 23), KMT2A partial tandem duplication (n = 11), rearrangements involving MECOM (n = 7), NUP98 (n = 2), KMT2A (n = 2), JAK2 (n = 2), and other gene fusions in 17 patients, with 10 showing novel fusion gene partners. OGM also pinpointed fusion genes in 17 (11%) patients where chromosomal rearrangements were concurrently detected by OGM and CBA. Overall, 24 (15%) aberrations were identified exclusively by OGM and had the potential to alter AML classification, risk stratification, and/or clinical trial eligibility. OGM emerges as a powerful tool for identifying fusion genes and detecting subtle or cryptic cytogenomic aberrations that may otherwise remain undetectable by CBA.

细胞基因组学特征对于急性髓性白血病（AML）的分类和风险分层至关重要，从而有助于做出治疗决策。我们研究了光学基因组图谱（OGM）在 159 例急性髓性白血病患者（103 例新诊断患者和 56 例难治/复发患者）中的临床应用，所有这些患者都接受了染色体条带分析（CBA）、荧光原位杂交和定向下一代测序。只要克隆负荷高于 20%，OGM 几乎能检测出 SCG 所发现的所有临床相关细胞遗传学异常，灵敏度高于 99%。OGM 在 77 例（48%）患者中发现了额外的细胞基因组畸变和/或提供了融合基因的信息，其中包括 8 例核型正常的患者和 4 例核型检测失败的患者。OGM 发现的最常见的额外改变包括染色体畸变（23 例）、KMT2A 部分串联重复（11 例）、涉及 MECOM（7 例）、NUP98（2 例）、KMT2A（2 例）、JAK2（2 例）的重排，以及 17 例患者的其他基因融合，其中 10 例显示了新的融合基因伙伴。在 17 例（11%）同时通过 OGM 和 CBA 检测到染色体重排的患者中，OGM 也精确定位了融合基因。总体而言，有 24 例（15%）畸变完全由 OGM 确定，有可能改变急性髓细胞性白血病的分类、风险分层和/或临床试验资格。OGM是鉴定融合基因和检测微小或隐蔽细胞基因组畸变的有力工具，否则CBA可能无法检测到这些畸变。

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引用次数: 0

Frontline therapy of acute myeloid leukemia with lower intensity regimens: Where are we now and where can we go? 用低强度疗法对急性髓性白血病进行一线治疗：我们的现状和未来？

IF 10.1 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2024-07-17 DOI: 10.1002/ajh.27434

Jennifer Marvin-Peek, Jason S. Gilbert, Daniel A. Pollyea, Courtney D. DiNardo

The advent of molecularly targeted therapeutics has transformed the management of patients with acute myeloid leukemia (AML). Particularly for individuals unfit for intensive chemotherapy, lower intensity therapies (LIT) incorporating small molecules have significantly improved patient outcomes. With BCL2, IDH1, IDH2, and FLT3 inhibitors widely used for relapsed AML, combination regimens are now utilized in the frontline. Expansion of these targeted LIT combinations, along with development of novel agents including menin inhibitors, exemplifies the promise of precision medicine. Further understanding of molecular drivers of leukemic transformation and mechanisms of relapse will continue to advance frontline treatment options for patients with AML.

分子靶向疗法的出现改变了急性髓性白血病（AML）患者的治疗方法。特别是对于不适合接受强化化疗的患者，结合小分子药物的低强度疗法（LIT）显著改善了患者的预后。随着BCL2、IDH1、IDH2和FLT3抑制剂被广泛用于治疗复发的急性髓细胞白血病，联合疗法现已被用于一线治疗。随着包括 menin 抑制剂在内的新型药物的开发，这些有针对性的 LIT 组合疗法的推广体现了精准医疗的前景。对白血病转化的分子驱动因素和复发机制的进一步了解将继续推动急性髓细胞性白血病患者一线治疗方案的发展。

引用次数: 0

Correction to “Natural history, predictors of development of extramedullary disease, and treatment outcomes for patients with extramedullary multiple myeloma” 对 "髓外多发性骨髓瘤患者的自然病史、髓外疾病发展的预测因素和治疗效果 "的更正。

IF 10.1 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2024-07-12 DOI: 10.1002/ajh.27403

Zanwar S, Ho M, Lin Y, Kapoor P, Binder M, Buadi FK, Dispenzieri A, Dingli D, Fonder A, Gertz MA, Gonsalves W, Hayman SR, Hwa Y, Hobbs M, Kourelis T, Lacy MQ, Leung N, Muchtar E, Warsame R, Jevremovic D, Kyle RA, Rajkumar SV, Kumar S. Am J Hematol. 2023 Oct;98(10):1540–1549. doi: 10.1002/ajh.27023. Epub 2023 Jul 8. PMID: 37421603.

In this article, we forgot to acknowledge that the work was supported by the Paul Calabresi K12 Career Development Award (CA90628-21).

We apologize for this error.

Zanwar S, Ho M, Lin Y, Kapoor P, Binder M, Buadi FK, Dispenzieri A, Dingli D, Fonder A, Gertz MA, Gonsalves W, Hayman SR, Hwa Y, Hobbs M, Kourelis T, Lacy MQ, Leung N, Muchtar E, Warsame R, Jevremovic D, Kyle RA, Rajkumar SV, Kumar S. Am J Hematol.DOI: 10.1002/ajh.27023.Epub 2023 Jul 8. PMID: 37421603.在这篇文章中，我们忘了承认这项工作得到了保罗-卡拉布雷西 K12 职业发展奖（CA90628-21）的支持，对此我们深表歉意。

引用次数: 0

Correction to “Risk factors for severe infection and mortality in patients with COVID-19 in patients with multiple myeloma and AL amyloidosis” 更正 "多发性骨髓瘤和 AL 淀粉样变性患者中 COVID-19 患者严重感染和死亡的风险因素"。

IF 10.1 1区医学 Q1 HEMATOLOGY

American Journal of Hematology

Pub Date : 2024-07-12 DOI: 10.1002/ajh.27402

Ho M, Zanwar S, Buadi FK, Ailawadhi S, Larsen J, Bergsagel L, Binder M, Chanan-Khan A, Dingli D, Dispenzieri A, Fonseca R, Gertz MA, Gonsalves W, Go RS, Hayman S, Kapoor P, Kourelis T, Lacy MQ, Leung N, Lin Y, Muchtar E, Roy V, Sher T, Warsame R, Fonder A, Hobbs M, Hwa YL, Kyle RA, Rajkumar SV, Kumar S. Am J Hematol. 2023 Jan;98(1):49–55. doi: 10.1002/ajh.26762. Epub 2022 Oct 24. PMID: 36226510.

In this article, we forgot to acknowledge that the work was supported by the Paul Calabresi K12 Career Development Award (CA90628-21).

We apologize for this error.

Ho M、Zanwar S、Buadi FK、Ailawadhi S、Larsen J、Bergsagel L、Binder M、Chanan-Khan A、Dingli D、Dispenzieri A、Fonseca R、Gertz MA、Gonsalves W、Go RS、Hayman S、Kapoor P、Kourelis T、Lacy MQ、Leung N、Lin Y、Muchtar E、Roy V、Sher T、Warsame R、Fonder A、Hobbs M、Hwa YL、Kyle RA、Rajkumar SV、Kumar S。Am J Hematol.DOI: 10.1002/ajh.26762.Epub 2022 Oct 24.PMID: 36226510.在这篇文章中，我们忘了承认这项工作得到了保罗-卡拉布雷西 K12 职业发展奖（CA90628-21）的支持。

引用次数: 0