BCL-2 Inhibition as Treatment for Chronic Lymphocytic Leukemia.

IF 3.8 2区 医学 Q2 ONCOLOGY
Guilherme Fleury Perini, Carolina Cristina Pellegrino Feres, Larissa Lane Cardoso Teixeira, Nelson Hamerschlak
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引用次数: 13

Abstract

Opinion statement: At the end of the 1990s, with the advent of imatinib for chronic myeloid leukemia and rituximab for B cell lymphoproliferative diseases with CD20 expression, there was a great conceptual evolution in the treatment of onco-hematological diseases. Researchers from around the world and the pharmaceutical industry began to focus their efforts on the so-called target therapy used alone or associated with classic chemotherapeutic drugs. In chronic lymphocytic leukemia, the development of second-generation anti-CD20 antibodies, biosimilars, PI3K (phosphatidylinositol 3-kinases) inhibitors, BTK (Bruton's tyrosine kinase) inhibitors, and anti-bcl 2 drugs represented mainly by venetoclax brought new, broader, and more effective opportunities in the treatment of this disease. This breakthrough occurred mainly regarding patients with alteration in 17p or mutation of the p53 gene for whom selecting the new drugs that act on B cell signaling (BTK and PI3K inhibitors) in the first line is mandatory. In fit patients with immunoglobulin heavy chain mutation, it is still acceptable to use the chemotherapy regimen with fludarabine, cyclophosphamide, and rituximab (FCR) and, in those who do not fit or are not IgVH-mutated, bendamustine-rituximab regimen. However, the first-line use of ibrutinib or venetoclax associated with immunotherapy within the concepts of infinite (ibrutinib) or finite (venetoclax) treatment has been increasingly used. In the second line, venetoclax, ibrutinib, and idelalisib have become the preferred treatments. I believe that a process of instruction and decision shared with patients considering the risks-benefits-cost and access to treatments should guide the choices within these concepts. Another fundamental aspect to discuss is the objective of the treatment for chronic lymphocytic leukemia (CLL) for a specific patient: the increase progression-free survival and overall survival and/or the achievement of minimal residual disease. CLL is the most common leukemia in adults with a median age at diagnosis of 72 years. The clinical course is heterogeneous, and outcomes are influenced by individual clinical presentation and disease biology. Molecular and genomic factors, including fluorescence in situ hybridization (FISH) testing, karyotype, and immunoglobulin heavy chain variable region gene (IGHV) mutational status, are important to treatment decisions and to predict the clinical course. However, despite disease biology, the presence of active disease is the most important criteria to initiate treatment. In the past decade, target therapies that inhibit B cell receptor signaling pathways and, more recently, BCL2 antagonists have emerged as a new treatment paradigm: chemo-free with fixed duration therapy. Bruton's tyrosine kinase inhibitors (BTK) are a class of oral medications approved for frontline and relapsed disease, effective for achieving lasting response and disease control with a good safety profile. BTK inhibitors are an attractive option for high-risk patients who are not candidates for an intensive regimen. However, it is a continuous therapy, and drug resistance or severe adverse events could lead to treatment suspension. BCL2 antagonists are an attractive alternative to BTK inhibitors. Anti-apoptotic BCL2 is associated with tumor genesis and chemotherapy resistance. The BCl2, an anti-apoptotic protein located in the mitochondrial membrane, is a major contributor to the pathogenesis of lymphoid malignancies and is overexpressed in CLL cells promoting clonal cell survival. Venetoclax is a potent and selective member of the BH3 mimetic drugs and a physiologic antagonist of BCL2. Venetoclax has demonstrated quick and durable responses in naïve and relapsed or refractory CLL (r/r CLL) patients, including high-risk patients. Furthermore, it has shown deeper responses, achieving a higher incidence of negative minimal residual disease (MRD) with a fixed duration therapy. In the past decade, there was a remarkable progress in CLL treatment. However, neither of the new target therapies is considered curative or free of toxicity. This article will focus on the treatment approach of CLL patients with BCl2 antagonists. Treatment strategy (combined versus monotherapy; continuous versus limited duration therapy), toxicity profile, and future directions will be exposed in this review.

BCL-2抑制治疗慢性淋巴细胞白血病。
观点声明:20世纪90年代末,随着伊马替尼治疗慢性髓系白血病和利妥昔单抗治疗CD20表达的B细胞淋巴增殖性疾病的出现,肿瘤血液系统疾病的治疗有了很大的概念演变。来自世界各地和制药行业的研究人员开始将精力集中在所谓的靶向治疗上,即单独使用或与经典化疗药物联合使用。在慢性淋巴细胞白血病中,第二代抗cd20抗体、生物仿制药、PI3K(磷脂酰肌醇3-激酶)抑制剂、BTK(布鲁顿酪氨酸激酶)抑制剂以及以venetoclax为代表的抗bcl - 2药物的开发,为慢性淋巴细胞白血病的治疗带来了新的、更广泛、更有效的机会。这一突破主要发生在17p基因改变或p53基因突变的患者身上,对于这些患者,必须在一线选择作用于B细胞信号传导的新药(BTK和PI3K抑制剂)。在适合的免疫球蛋白重链突变患者中,仍然可以使用氟达拉滨、环磷酰胺和利妥昔单抗(FCR)的化疗方案,而在不适合或没有igvh突变的患者中,可以使用苯达莫司汀-利妥昔单抗方案。然而,在无限(伊鲁替尼)或有限(venetoclax)治疗的概念中,一线使用伊鲁替尼或venetoclax与免疫治疗相关的治疗已经越来越多地使用。在二线,venetoclax, ibrutinib和ideelalisib已成为首选的治疗方法。我认为,与患者共同考虑风险-收益-成本和获得治疗的机会的指导和决策过程应该在这些概念中指导选择。要讨论的另一个基本方面是针对特定患者的慢性淋巴细胞白血病(CLL)的治疗目标:增加无进展生存期和总生存期和/或实现最小残留疾病。CLL是成人中最常见的白血病,诊断时的中位年龄为72岁。临床过程是异质性的,结果受个体临床表现和疾病生物学的影响。分子和基因组因素,包括荧光原位杂交(FISH)检测、核型和免疫球蛋白重链可变区基因(IGHV)突变状态,对治疗决策和预测临床病程很重要。然而,尽管疾病生物学,活动性疾病的存在是开始治疗的最重要标准。在过去的十年中,抑制B细胞受体信号通路的靶向治疗以及最近的BCL2拮抗剂已经成为一种新的治疗模式:无化疗和固定持续时间的治疗。Bruton的酪氨酸激酶抑制剂(BTK)是一类被批准用于一线和复发疾病的口服药物,有效地实现持久的反应和疾病控制,具有良好的安全性。BTK抑制剂对于不适合强化治疗方案的高危患者是一个有吸引力的选择。然而,它是一个持续的治疗,耐药或严重的不良事件可能导致治疗暂停。BCL2拮抗剂是BTK抑制剂的一个有吸引力的替代品。抗凋亡BCL2与肿瘤发生和化疗耐药有关。BCl2是一种位于线粒体膜上的抗凋亡蛋白,是淋巴细胞恶性肿瘤发病的主要因素,在CLL细胞中过表达,促进克隆细胞存活。Venetoclax是BCL2的生理性拮抗剂和BH3模拟药物的有效和选择性成员。Venetoclax在naïve和复发或难治性CLL (r/r CLL)患者(包括高风险患者)中表现出快速和持久的反应。此外,它已显示出更深层次的反应,在固定持续时间的治疗下实现更高的负最小残留病(MRD)发生率。在过去的十年里,CLL的治疗取得了显著的进展。然而,这两种新的靶向疗法都不被认为是治愈或无毒的。本文将重点讨论BCl2拮抗剂治疗CLL患者的方法。治疗策略(联合与单药治疗;持续与有限时间治疗),毒性概况和未来的方向将在这篇综述中暴露。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.10
自引率
0.00%
发文量
113
审稿时长
>12 weeks
期刊介绍: This journal aims to review the most important, recently published treatment option advances in the field of oncology. By providing clear, insightful, balanced contributions by international experts, the journal intends to facilitate worldwide approaches to cancer treatment. We accomplish this aim by appointing international authorities to serve as Section Editors in key subject areas, such as endocrine tumors, lymphomas, neuro-oncology, and cancers of the breast, head and neck, lung, skin, gastrointestinal tract, and genitourinary region. Section Editors, in turn, select topics for which leading experts contribute comprehensive review articles that emphasize new developments and recently published papers of major importance, highlighted by annotated reference lists. We also provide commentaries from well-known oncologists, and an international Editorial Board reviews the annual table of contents, suggests articles of special interest to their country/region, and ensures that topics are current and include emerging research.
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