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Zanubrutinib for the Treatment of B-cell Malignancies 扎鲁替尼治疗b细胞恶性肿瘤
Pub Date : 2022-01-01 DOI: 10.17925/ohr.2022.18.1.44
A. Rosenthal, J. Muñoz
Selective Bruton's tyrosine kinase (BTK) inhibition is an important therapeutic approach for B-cell malignancies. Ibrutinib, a first-in-class, oral, irreversible BTK inhibitor, has a toxicity profile attributed to off-target inhibition of kinases structurally related to BTK. A highly potent and selective next-generation BTK inhibitor, zanubrutinib, was designed to address intolerance and toxicity concerns associated with ibrutinib. Zanubrutinib provides complete and sustained BTK occupancy in peripheral blood mononuclear cells and lymph nodes, with reduced toxicity compared with ibrutinib. Zanubrutinib received accelerated approval in the USA for patients with previously treated mantle cell lymphoma (2019) and relapsed/refractory (R/R) marginal zone lymphoma (2021) and was approved for Waldenström's macroglobulinaemia (WM) in 2021. Key clinical trials evaluating the efficacy and safety of zanubrutinib include the ASPEN study in patients with WM (ClinicalTrials.gov identifier: NCT03053440), the ALPINE study in patients with R/R chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL; ClinicalTrials.gov identifier: NCT03734016) and the SEQUOIA study in treatment-naïve patients with CLL/SLL with and without del(17p) mutation (ClinicalTrials.gov identifier: NCT03336333). The more selective BTK binding profile, high potency, favourable pharmacokinetic and pharmacodynamic profile, and minimal cardiovascular toxicity of zanubrutinib compared with ibrutinib suggest that zanubrutinib may be an important treatment option when prescribed in accordance with guidelines.
选择性抑制布鲁顿酪氨酸激酶(BTK)是治疗b细胞恶性肿瘤的重要方法。Ibrutinib是一种一流的口服不可逆BTK抑制剂,其毒性特征归因于与BTK结构相关的激酶的脱靶抑制。一种高效和选择性的下一代BTK抑制剂zanubrutinib被设计用于解决与ibrutinib相关的不耐受和毒性问题。Zanubrutinib在外周血单个核细胞和淋巴结中提供完全和持续的BTK占用,与依鲁替尼相比毒性降低。Zanubrutinib在美国获得加速批准,用于先前治疗的套细胞淋巴瘤(2019)和复发/难治性(R/R)边缘区淋巴瘤(2021)患者,并于2021年获批用于Waldenström的巨球蛋白血症(WM)。评估扎鲁替尼疗效和安全性的关键临床试验包括WM患者的ASPEN研究(ClinicalTrials.gov标识:NCT03053440), R/R慢性淋巴细胞性白血病(CLL)或小淋巴细胞性淋巴瘤(SLL)患者的ALPINE研究;ClinicalTrials.gov识别码:NCT03734016)和SEQUOIA研究treatment-naïve伴有和不伴有del(17p)突变的CLL/SLL患者(ClinicalTrials.gov识别码:NCT03336333)。与依鲁替尼相比,zanubrutinib更具选择性的BTK结合谱、高效力、有利的药代动力学和药效学谱以及最小的心血管毒性表明,在按照指南处方的情况下,zanubrutinib可能是一个重要的治疗选择。
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引用次数: 2
COVID Coagulopathy and Thrombosis: A Systematic Review COVID - 19凝血功能障碍和血栓形成:系统综述
Pub Date : 1900-01-01 DOI: 10.17925/ohr.2022.18.1.78
R. Asrani, W. Bahou
Introduction: Since the onset of the SARS-CoV-2 pandemic, haematological laboratory abnormalities and thrombotic complications have been observed among infected patients. We aimed to highlight key pathophysiological mechanisms of COVID-19-associated coagulopathy and to summarize incidence rates of venous and arterial thrombotic events, comorbidities conferring risk, and current treatment guidelines including data from ongoing clinical trials. Methods: A systematic review was performed according to PRISMA recommendations of case–control studies, cohort studies, observational studies and randomized clinical trials (RCTs) published between 1 December 2019 and 30 September 2021 within PubMed and Web of Science. Inclusion criteria were English language, adult patients and at least one coagulation parameter described. Results: 2,554 records were screened, from which 59 studies were included. Abnormalities in several laboratory parameters were associated with worse clinical outcomes including elevations in prothrombin time, activated partial thromboplastin time, D-dimer, fibrinogen, von Willebrand factor antigen/activity and lupus anticoagulant antibodies. Rates of venous and arterial thromboembolism varied significantly among studies performed early in the pandemic and across different nations. Pathophysiological mechanisms included vascular endotheliopathy, increased inflammation and macrophage activation, neutrophil extracellular traps, antiphospholipid antibody production and obesity/adipose tissue signalling. Current recommendations for management of COVID coagulopathy from various societies include the use and dosing of systemic anticoagulation to prevent thrombotic sequelae in the outpatient, inpatient and critical care settings. The optimal anticoagulant dose for thromboprophylaxis in the inpatient and critical care settings is currently not well established. Conclusions: SARS-CoV-2 infection can cause a distinct form of coagulopathy, with thromboembolic complications leading to significant morbidity and mortality. The optimal treatment requires further refinement pending the results from key ongoing RCTs
自SARS-CoV-2大流行开始以来,在感染患者中观察到血液学实验室异常和血栓并发症。我们旨在强调covid -19相关凝血病的关键病理生理机制,并总结静脉和动脉血栓形成事件的发生率、具有风险的合并症以及目前的治疗指南,包括来自正在进行的临床试验的数据。方法:根据PRISMA的建议,对2019年12月1日至2021年9月30日在PubMed和Web of Science上发表的病例对照研究、队列研究、观察性研究和随机临床试验(rct)进行系统评价。纳入标准为英语、成年患者和至少描述一个凝血参数。结果:2554份记录被筛选,其中包括59项研究。一些实验室参数的异常与较差的临床结果相关,包括凝血酶原时间、活化的部分凝血活酶时间、d -二聚体、纤维蛋白原、血管性血友病因子抗原/活性和狼疮抗凝抗体的升高。在大流行早期和不同国家进行的研究中,静脉和动脉血栓栓塞率差异很大。病理生理机制包括血管内皮病变、炎症和巨噬细胞活化增加、中性粒细胞胞外陷阱、抗磷脂抗体产生和肥胖/脂肪组织信号传导。目前来自不同学会的关于COVID - 19凝血病管理的建议包括在门诊、住院和重症监护环境中使用和剂量全身性抗凝治疗以预防血栓后遗症。在住院和重症监护环境中预防血栓的最佳抗凝剂量目前还没有很好地确定。结论:SARS-CoV-2感染可引起不同形式的凝血功能障碍,伴有血栓栓塞并发症,导致显著的发病率和死亡率。在关键的随机对照试验结果出来之前,最佳治疗方案需要进一步完善
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引用次数: 2
Current and Future Therapies for Marginal Zone Lymphoma 边缘区淋巴瘤目前和未来的治疗方法
Pub Date : 1900-01-01 DOI: 10.17925/ohr.2022.18.1.40
N. Chilakamarri, Karla Olmedo, E. Brem
Marginal zone lymphoma (MZL) is an indolent non-Hodgkin lymphoma with three subtypes: nodal, extranodal and splenic. Initial therapies can vary based on the subtype of MZL, location of disease and stage of disease. Treatment of MZL in the relapsed refractory (R/R) setting has evolved in recent years with the approvals of Bruton's tyrosine kinase inhibitors, phosphoinositide 3-kinase inhibitors and an immune modulatory drug, lenalidomide. Questions remain as to how best to use these agents to maximize efficacy and minimize toxicity. In this article, we focus on the management of MZL with currently available agents, particularly in the R/R setting. We also examine the therapies that may further change the treatment paradigm for MZL. Specifically, we discuss the available data for chimeric antigen receptor T-cell therapies and CD20–CD3 bispecific antibodies, and consider the limitations and potential benefits of these approaches.
边缘带淋巴瘤(MZL)是一种无痛的非霍奇金淋巴瘤,有三种亚型:淋巴结、结外和脾。初始治疗可以根据MZL的亚型、疾病的位置和疾病的阶段而有所不同。近年来,随着Bruton的酪氨酸激酶抑制剂、磷酸肌苷3-激酶抑制剂和免疫调节药物来那度胺的批准,复发难治(R/R) MZL的治疗已经发生了变化。问题仍然是如何最好地使用这些药物,以最大限度地提高疗效和减少毒性。在本文中,我们将重点讨论使用当前可用的代理管理MZL,特别是在R/R设置中。我们还研究了可能进一步改变MZL治疗模式的治疗方法。具体来说,我们讨论了嵌合抗原受体t细胞疗法和CD20-CD3双特异性抗体的可用数据,并考虑了这些方法的局限性和潜在益处。
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引用次数: 1
Trastuzumab Deruxtecan for the Treatment of HER2-positive Breast Cancer Trastuzumab Deruxtecan用于治疗her2阳性乳腺癌
Pub Date : 1900-01-01 DOI: 10.17925/ohr.2023.19.1.6
T. Yamashita
Trastuzumab deruxtecan (T-DXd) is a new-generation anti-human epidermal growth factor receptor 2 (HER2) antibody–drug conjugate that has demonstrated good efficacy due to its stable linker, high drug–antibody ratio, and high bystander effect resulting from the efficient cell membrane permeability of its payload. The DESTINY-Breast01 trial showed a response rate of >60% in patients with HER2-positive advanced recurrent breast cancer who had received a median of six regimens of prior therapy. The DESTINY-Breast03 trial, which compared T-DXd with trastuzumab emtansine (T-DM1) in HER2-positive unresectable and/or metastatic breast cancer also showed very high efficacy. Although T-DXd is highly effective, it is associated with a greater incidence of interstitial pneumonia than conventional anti-HER2 agents such as T-DM1. HER2-positive breast cancer frequently develops brain metastases, the drug therapy for which has had extremely limited success. Recently, however, in a small number of trials, T-DXd has been reported to be effective against brain metastasis, by shrinking BM.
Trastuzumab deruxtecan (T-DXd)是新一代抗人表皮生长因子受体2 (HER2)抗体-药物偶联物,其连接物稳定,药抗比高,有效载荷的细胞膜通透性高,旁观者效应高,具有良好的疗效。DESTINY-Breast01试验显示,her2阳性晚期复发性乳腺癌患者既往接受过中位数6种治疗方案的应答率>60%。DESTINY-Breast03试验比较了T-DXd与曲妥珠单抗emtansine (T-DM1)在her2阳性不可切除和/或转移性乳腺癌中的疗效,也显示出非常高的疗效。尽管T-DXd非常有效,但与传统的抗her2药物(如T-DM1)相比,它与间质性肺炎的发病率更高相关。her2阳性乳腺癌经常发生脑转移,这种药物治疗的效果非常有限。然而,最近在少数试验中,据报道T-DXd通过缩小脑转移瘤对脑转移有效。
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引用次数: 0
Use of Circulating Tumour DNA to Assess Minimal Residual Disease in Gastrointestinal Cancers 利用循环肿瘤DNA评估胃肠道肿瘤的微小残留病变
Pub Date : 1900-01-01 DOI: 10.17925/ohr.2022.18.1.26
Reetu Mukherji, Ali J Alqahtani, Harrison D. Winters, B. Weinberg
Despite our modern perioperative therapies, many patients with gastrointestinal cancer relapse after surgery. Novel strategies to identify and treat patients at high risk of relapse are needed to improve cancer outcomes. Circulating tumour DNA (ctDNA) is a promising, non-invasive biomarker with the potential to identify the earliest signs of cancer relapse. The presence of tumourspecific DNA in the blood in the absence of visualized tumour is suggestive of minimal residual disease and forebodes measurable relapse. Genomic sequencing techniques have advanced over the past few decades, and we have become better able to detect significantly low levels of DNA circulating in the blood from low-volume disease. Numerous studies using various technologies have established ctDNA as a powerful prognostic biomarker for relapse and survival in gastrointestinal cancers. ctDNA has the potential to risk-stratify patients in the postoperative, post-adjuvant and longitudinal settings for therapeutic escalation or de-escalation strategies. It may also capture early tumour dynamics in response to therapeutic intervention. As the multifaceted potential of ctDNA is attracting the attention of researchers, clinicians and patients, many questions remain regarding its use, interpretation and limitations. Here, we discuss the current understanding of ctDNA for minimal residual disease evaluation in gastrointestinal cancers and potential future directions.
尽管我们的现代围手术期治疗,许多胃肠道肿瘤患者术后复发。需要新的策略来识别和治疗复发风险高的患者,以改善癌症预后。循环肿瘤DNA (ctDNA)是一种很有前途的非侵入性生物标志物,具有识别癌症复发早期迹象的潜力。在没有可见肿瘤的情况下,血液中肿瘤特异性DNA的存在提示疾病残留很小,预示着可测量的复发。在过去的几十年里,基因组测序技术已经取得了进步,我们已经能够更好地检测血液中循环的低水平DNA,这些DNA来自低容量疾病。使用各种技术的大量研究已经确定ctDNA是胃肠道癌症复发和生存的强大预后生物标志物。ctDNA有可能在术后、辅助后和纵向环境中对患者进行风险分层,以确定治疗升级或降级策略。它也可以捕捉早期肿瘤动力学对治疗干预的反应。随着ctDNA多方面的潜力吸引了研究人员、临床医生和患者的注意,关于其使用、解释和局限性仍存在许多问题。在这里,我们讨论了目前对ctDNA用于胃肠道癌症最小残留疾病评估的理解和潜在的未来方向。
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引用次数: 0
Pembrolizumab and Chemotherapy in Cervical Cancer: A New Standard of Care? 宫颈癌的派姆单抗和化疗:一个新的治疗标准?
Pub Date : 1900-01-01 DOI: 10.17925/ohr.2022.18.1.2
C. Lebreton, O. Saux, B. Mery, M. Bini, C. Romeo, I. Ray-Coquard
Cervical cancer (CC) still has a high incidence despite screening programmes and access to human papillomavirus (HPV) vaccination, with a poor prognosis in the advanced setting. Most cases of cervical carcinoma are related to HPV infection. The pathogen-induced nature of the disease, the involvement of genes regulating the immune response and the high grade of immune infiltration provide the rationale to evaluate anti-programmed death-(ligand)1 (PD-[L]1) immune checkpoint inhibitors in CC. This article reviews the promising outcomes of the KEYNOTE-826 phase III trial, which evaluates the addition of pembrolizumab to chemotherapy in patients with PD-L1-positive disease and recurrent, persistent or metastatic cancer of the cervix, leading to an improvement of progression-free survival and overall survival. We also aim to address some outstanding questions and discuss the next steps in immunotherapy for CC.
尽管有筛查计划和人乳头瘤病毒(HPV)疫苗接种,但宫颈癌(CC)的发病率仍然很高,在晚期环境中预后较差。大多数宫颈癌病例与HPV感染有关。该疾病的病原体诱导性质、调节免疫反应的基因的参与和高度免疫浸润为评估CC中抗程序性死亡-(配体)1 (PD-[L]1)免疫检查点抑制剂提供了基本原理。本文回顾了KEYNOTE-826 III期试验的前景,该试验评估了PD- l1阳性疾病和复发、持续性或转移性宫颈癌患者在化疗中添加派姆单抗的结果。导致无进展生存期和总生存期的改善。我们还旨在解决一些悬而未决的问题,并讨论CC免疫治疗的下一步。
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引用次数: 0
Updates in the Management of Multiple Myeloma from the American Society of Hematology Meeting 2021 来自2021年美国血液学会会议的多发性骨髓瘤管理的最新进展
Pub Date : 1900-01-01 DOI: 10.17925/ohr.2022.18.1.53
S. Vasudevan, Sravani Gundarlapalli, N. Thalambedu, Meera Mohan
Multiple myeloma (MM) remains largely an incurable disease with only a small percentage of patients achieving long-term remission. Here, we highlight some of the major studies on MM presented at the American Society of Hematology meeting in December 2021. Early results of the first ever population-based screening studies for precursor states of MM, iStopMM and PROMISE, were reported. These studies will inform on the risks and benefits of screening in MM and could lead to a paradigm shift towards screening and early therapy. In newly diagnosed MM, there were promising data on quadruple therapy with addition of a monoclonal antibody against the CD38 antigen to the existing backbone of lenalidomide, bortezomib and dexamethasone. T-cell–directed therapy including bispecific antibody and chimeric antigen receptor therapy demonstrated high clinical response, especially in triple-class refractory myeloma. We acknowledge that this review focuses on some exciting studies in both precursor and active MM and is not comprehensive by any means.
多发性骨髓瘤(MM)在很大程度上仍然是一种无法治愈的疾病,只有一小部分患者获得长期缓解。在这里,我们重点介绍了2021年12月美国血液学学会会议上发表的一些关于MM的主要研究。报道了首次以人群为基础的MM前体状态(iStopMM和PROMISE)筛查研究的早期结果。这些研究将告知MM筛查的风险和益处,并可能导致向筛查和早期治疗的范式转变。在新诊断的MM中,在现有的来那度胺、硼替佐米和地塞米松主干中添加一种抗CD38抗原的单克隆抗体的四联治疗有希望的数据。包括双特异性抗体和嵌合抗原受体在内的t细胞定向治疗显示出很高的临床疗效,特别是在三级难治性骨髓瘤中。我们承认这篇综述集中在前体和活性MM的一些令人兴奋的研究,无论如何都不全面。
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引用次数: 0
Pafolacianine: A Diagnostic Agent to Identify Lung Cancer Lesions in Adults with Known or Suspected Lung Cancer Pafolacianine:一种识别已知或疑似肺癌成人肺癌病灶的诊断剂
Pub Date : 1900-01-01 DOI: 10.17925/ohr.2023.19.1.2
L. Martin

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引用次数: 0
ATLAS: Risk-adapted Triplet Maintenance with Carfilzomib, Lenalidomide and Dexamethasone – Still Shrugging? ATLAS:卡非佐米、来那度胺和地塞米松的风险适应三联维持-仍在耸耸肩?
Pub Date : 1900-01-01 DOI: 10.17925/ohr.2022.18.2.96
Joseph K Franz, S. Lonial
ATLAS (ClinicalTrials.gov Identifier: NCT02659293) is a randomized phase III clinical trial comparing intensified carfilzomib, lenalidomide and dexamethasone (KRd) maintenance to standard-of-care, single-agent lenalidomide. The recently reported primary analysis showed a progression-free survival benefit for KRd. Whilst the study met its primary endpoint, closer analysis of its design and results is necessary before this intensified maintenance strategy can be adopted in clinical practice.
ATLAS (ClinicalTrials.gov识别码:NCT02659293)是一项随机III期临床试验,比较强化卡非佐米、来那度胺和地塞米松(KRd)维持与标准护理单药来那度胺的疗效。最近报道的初步分析显示,KRd的无进展生存期获益。虽然该研究达到了主要终点,但在临床实践中采用这种强化维持策略之前,有必要对其设计和结果进行更深入的分析。
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引用次数: 0
Is Triple Therapy the New Standard for Metastatic Hormone-sensitive Prostate Cancer? 三联疗法是治疗转移性激素敏感前列腺癌的新标准吗?
Pub Date : 1900-01-01 DOI: 10.17925/ohr.2022.18.2.120
J. Hack, S. Crabb
The treatment of metastatic hormone-sensitive prostate cancer has rapidly changed over the last decade. Currently, standard of care (SOC) options for first-line treatment are androgen deprivation therapy (ADT) in combination with either docetaxel chemotherapy or an androgen receptor pathway inhibitor such as abiraterone, enzalutamide or apalutamide. Recent results from both the PEACE-1 and ARASENS trials show an overall survival and progression-free survival benefit from the addition of an androgen-receptor pathway inhibitor for patients in whom the SOC option of ADT plus docetaxel has been chosen in de novo metastatic hormone-sensitive prostate cancer, with a more pronounced benefit in those with high-volume metastatic disease. However, many clinicians now preferentially use ADT plus an androgen-receptor pathway inhibitor as SOC first-line treatment, and no prospective trial has addressed whether there is a benefit from the addition of docetaxel to this version of SOC combination therapy. The benefit of triplet combination therapy in those with recurrent or low-volume metastatic disease is less clear and longer follow-up is required before conclusions can be drawn about these patient groups.
在过去十年中,转移性激素敏感前列腺癌的治疗方法发生了迅速的变化。目前,一线治疗的标准护理(SOC)选择是雄激素剥夺疗法(ADT)联合多西紫杉醇化疗或雄激素受体途径抑制剂,如阿比特龙、恩杂鲁胺或阿帕鲁胺。PEACE-1和ARASENS试验的最新结果显示,对于新发转移性激素敏感前列腺癌患者,如果选择了ADT +多西他赛的SOC选项,则添加雄激素受体途径抑制剂可提高总生存期和无进展生存期,对于那些高转移性疾病的患者,获益更为明显。然而,许多临床医生现在优先使用ADT加雄激素受体途径抑制剂作为SOC的一线治疗,并且没有前瞻性试验表明在这种版本的SOC联合治疗中添加多西他赛是否有好处。三联疗法对复发性或小体积转移性疾病患者的益处尚不清楚,需要更长的随访时间才能得出关于这些患者群体的结论。
{"title":"Is Triple Therapy the New Standard for Metastatic Hormone-sensitive Prostate Cancer?","authors":"J. Hack, S. Crabb","doi":"10.17925/ohr.2022.18.2.120","DOIUrl":"https://doi.org/10.17925/ohr.2022.18.2.120","url":null,"abstract":"The treatment of metastatic hormone-sensitive prostate cancer has rapidly changed over the last decade. Currently, standard of care (SOC) options for first-line treatment are androgen deprivation therapy (ADT) in combination with either docetaxel chemotherapy or an androgen receptor pathway inhibitor such as abiraterone, enzalutamide or apalutamide. Recent results from both the PEACE-1 and ARASENS trials show an overall survival and progression-free survival benefit from the addition of an androgen-receptor pathway inhibitor for patients in whom the SOC option of ADT plus docetaxel has been chosen in de novo metastatic hormone-sensitive prostate cancer, with a more pronounced benefit in those with high-volume metastatic disease. However, many clinicians now preferentially use ADT plus an androgen-receptor pathway inhibitor as SOC first-line treatment, and no prospective trial has addressed whether there is a benefit from the addition of docetaxel to this version of SOC combination therapy. The benefit of triplet combination therapy in those with recurrent or low-volume metastatic disease is less clear and longer follow-up is required before conclusions can be drawn about these patient groups.","PeriodicalId":249239,"journal":{"name":"Oncology &amp; Haematology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134051253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Oncology &amp; Haematology
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