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  • 1.

    【2hr】Epigenetic therapy combinations in acute myeloid leukemia: what are the options?

    包量

    机译 表观遗传学治疗急性髓性白血病：有哪些选择？
    摘要：Epigenetics refers to the regulation of gene expression mainly by changes in DNA methylation and modifications of histone proteins without altering the actual DNA sequence. While epigenetic modifications are essential for normal cell differentiation, several driver mutations in leukemic pathogenesis have been identified in genes that affect epigenetic processes, such as DNA methylation and histone acetylation. Several therapeutic options to target epigenetic alterations in acute myeloid leukemia (AML) have been successfully tested in preclinical studies and various drugs have already been approved for use in clinical practice. Among these already approved therapeutics are hypomethylating agents (azacitidine and decitabine) and isocitrate dehydrogenase inhibitors (ivosidenib, enasidenib). Other agents such as bromodomain-containing epigenetic reader proteins and histone methylation (e.g. DOT1L) inhibitors are currently in advanced clinical testing. As several epigenetic therapies have only limited efficacy when used as single agents, combination therapies that target AML pathogenesis at different levels and exploit synergistic mechanisms are also in clinical trials. Combinations of either epigenetic therapies with conventional chemotherapy, different forms of epigenetic therapies, or epigenetic therapies with immunotherapy are showing promising early results. In this review we summarize the underlying pathophysiology and rationale for epigenetically-based combination therapies, review current preclinical and clinical data and discuss the future directions of epigenetic therapy combinations in AML.
  • 2.

    【2hr】A real-world comparative analysis of carfilzomib and other systemic multiple myeloma chemotherapies in a US community oncology setting

    包量

    机译 在美国社区肿瘤学中对卡非佐米和其他系统性多发性骨髓瘤化疗的真实比较分析
    摘要：Background:Most multiple myeloma (MM) patients ultimately progress, with remission duration decreasing after first relapse. Recently, novel agents have been approved for the treatment of relapsed MM. There is a paucity of real-world data on these treatments. We sought to compare time to next treatment (TTNT) in MM patients in their second line of therapy (LOT2), treated with common proteasome inhibitor (PI)-based triplets.
  • 3.

    【2hr】Novel treatment approaches and future perspectives in follicular lymphoma

    包量

    机译 滤泡性淋巴瘤的新治疗方法和未来展望
    摘要：Follicular lymphoma (FL) is a common B-cell malignancy characterized by relatively indolent growth and incurability with an expected lifetime course of serial intermittent treatment courses. Many patients with FL have lives shortened by the disease and despite a relatively favorable prognosis relative to other incurable systemic malignancies, optimal management of FL has not been achieved. This review focuses on identifying both patients for whom novel therapies might be most beneficial as well as systematically reviewing novel strategies at various levels of investigation. Prognostic markers incorporating clinical measurements and tumor genetics are discussed, yet at the time of diagnosis do not yet powerfully discriminate patients for whom specific strategies are beneficial. Reassessment of prognosis after evaluating the response to initial therapy is the most powerful identifier of those in need of novel management strategies. For initial therapy of high burden systemic disease, anti-CD20 antibody along with chemotherapy or immunomodulators all offer relatively similar effects on overall survival with subtly different effects on progression-free survival and quality of life. Several new agents currently under investigation in the upfront setting are discussed. Perhaps the best testing ground for novel therapies is in patients with early relapse following initial immunochemotherapy. Ongoing research in multiple therapy classes including, novel monoclonal antibodies, antibody drug conjugates, immunomodulatory agents, intracellular pathway inhibitors, immune checkpoint inhibitors, and epigenetic regulators are discussed herein.
  • 4.

    【2hr】Immunotherapy in myeloma: how far have we come?

    包量

    机译 骨髓瘤的免疫治疗：我们走了多远？
    摘要：The treatment of multiple myeloma (MM) has evolved substantially over the past decades, leading to a significantly improved outcome of MM patients. The introduction of high-dose therapy, especially, and autologous stem cell transplantation, as well as the development of new drugs, such as immunomodulatory drugs (IMiDs) and proteasome inhibitors have contributed to the improvement in survival. However, eventually most MM patients relapse, which indicates that there is a need for new agents and novel treatment strategies. Importantly, the long-term survival in a subset of MM patients after allogeneic stem cell transplantation illustrates the potential of immunotherapy in MM, but allogeneic stem cell transplantation is also associated with a high rate of treatment-related mortality. Recently, a better insight into several immune-evasion mechanisms, which contribute to tumor progression, has resulted in the development of active and well-tolerated novel forms of immunotherapy. These immunotherapeutic agents can be used as monotherapy, or, even more successfully, in combination with other established anti-MM agents to further improve depth and duration of response by preventing the outgrowth of resistant clones. This review will discuss the mechanisms used by MM cells to evade the immune system, and also provide an overview of currently approved immunotherapeutic drugs, such as IMiDs (e.g. lenalidomide and pomalidomide) and monoclonal antibodies that target cell surface antigens present on the MM cell (e.g. elotuzumab and daratumumab), as well as novel immunotherapies (e.g. chimeric antigen receptor T-cells, bispecific antibodies and checkpoint inhibitors) currently in clinical development in MM.
  • 5.

    【2hr】Insights into the optimal use of ponatinib in patients with chronic phase chronic myeloid leukaemia

    包量

    机译 对慢性期慢性粒细胞白血病患者最佳使用ponatinib的见解
    摘要：There are five tyrosine kinase inhibitors (TKIs) that are currently approved (in the European Union and the United States) for the treatment of chronic myeloid leukaemia (CML) in the chronic phase (CP) and each of them has its own efficacy and toxicity profile. Oral ponatinib (Iclusig®) is a third-generation TKI structurally designed to inhibit native BCR-ABL1 tyrosine kinase and several BCR-ABL1 mutants, including T315I. Ponatinib is now approved for patients with CML who are resistant or intolerant to prior TKI therapy (European Union) or for whom no other TKI therapy is indicated (United States). Despite achieving results in heavily treated patients, which led to its approval, the drug may induce cardiovascular events, requiring a careful baseline assessment of predisposing risk factors and specific management during treatment. Pharmacokinetic analysis has indicated the possibility of reducing the starting dose of ponatinib to 15 mg/day and preliminary data showed advantages in terms of safety while maintained its efficacy. This review summarizes the results achieved and drug-related side effects reported in all clinical trials and real-life experiences, testing ponatinib in patients with CP-CML. In addition, we focus on the appropriate use of ponatinib in clinical practice suggesting some useful recommendations on the proper management of this drug.
  • 6.

    【2hr】Emerging treatment paradigms with FLT3 inhibitors in acute myeloid leukemia

    包量

    机译 FLT3抑制剂在急性髓细胞白血病中的新兴治疗范例
    摘要：Mutations in the fms-like tyrosine kinase 3 (FLT3) gene are detected in approximately one-third of patients with newly diagnosed acute myeloid leukemia (AML). These consist of the more common FLT3-internal tandem duplication (ITD) in approximately 20–25% of AML cases, and point mutations in the tyrosine kinase domain (TKD) in approximately 5–10%. FLT3 mutations, especially FLT3-ITD, are associated with proliferative disease, increased risk of relapse, and inferior overall survival when treated with conventional regimens. However, the recent development of well tolerated and active FLT3 inhibitors has significantly improved the outcomes of this aggressive subtype of AML. The multikinase inhibitor midostaurin was approved by the United States Food and Drug Administration (US FDA) in April 2017 for the frontline treatment of patients with FLT3-mutated (either ITD or TKD) AML in combination with induction chemotherapy, representing the first new drug approval in AML in nearly two decades. In November 2018, the US FDA also approved the second-generation FLT3 inhibitor gilteritinib as a single agent for patients with relapsed or refractory FLT3-mutated AML. Promising phase I and II efficacy data for quizartinib is likely to lead to a third regulatory approval in relapsed/refractory AML in the near future. However, despite the significant progress made in managing FLT3-mutated AML, many questions remain regarding the best approach to integrate these inhibitors into combination regimens, and also the optimal sequencing of different FLT3 inhibitors in various clinical settings. This review comprehensively examines the FLT3 inhibitors currently in clinical development, with an emphasis on their spectra of activity against different FLT3 mutations and other kinases, clinical safety and efficacy data, and their current and future roles in the management of AML. The mechanisms of resistance to FLT3 inhibitors and potential combination strategies to overcome such resistance pathways are also discussed.
  • 7.

    【2hr】Switching thrombopoietin receptor agonist treatments in patients with primary immune thrombocytopenia

    包量

    机译 原发性免疫性血小板减少症患者的切换血小板生成素受体激动剂治疗
    摘要：Primary immune thrombocytopenia (ITP) is a bleeding disorder that conventionally has been treated with steroids or other immunosuppressive treatments. The introduction of thrombopoietin receptor agonists (TPO-RAs), which increase platelet production, dramatically changed the treatment landscape for ITP by providing patients with well-tolerated, long-term treatment options. Two TPO-RAs, eltrombopag and romiplostim, have been approved in the United States and European Union for the treatment of ITP. Some patients do not benefit from the first TPO-RA they receive, so it is assumed that the alternate TPO-RA would have the same outcome. However, eltrombopag and romiplostim have distinct pharmacodynamic and pharmacokinetic properties and may have different tolerability and efficacy in individual patients with ITP. Published retrospective studies showed that >75% of patients who switched to the alternate TPO-RA maintained or achieved a response with the new treatment. Notably, most patients who switched due to lack of efficacy with the first TPO-RA responded to the alternate TPO-RA, which demonstrates an absence of cross-resistance between the two drugs. Therefore, switching to the alternate TPO-RA if the first TPO-RA fails to demonstrate a response should be considered before the use of a less-preferable option.
  • 8.

    【2hr】Cost of peripheral neuropathy in patients receiving treatment formultiple myeloma: a US administrative claims analysis

    包量

    机译 接受以下药物治疗的患者周围神经病变的费用多发性骨髓瘤：美国一项行政要求分析
    摘要：Background:Peripheral neuropathy (PN) is a common consequence of multiple myeloma (MM) among those commonly treated with older-generation proteasome inhibitors (PIs). In this study, we evaluated the economic burden attributable to PN among MM patients in real-world practice settings in the US.
  • 9.

    【2hr】CAR T-cell therapy for B-cell lymphomas: clinical trial results ofavailable products

    包量

    机译 CAR T细胞疗法治疗B细胞淋巴瘤的临床试验结果可用产品
    摘要：Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cell has changed the treatment landscape of B-cell non-Hodgkin’s lymphoma (NHL), especially for aggressive B-cell lymphomas. Single-center and multicenter clinical trials with anti-CD19 CAR T-cell therapy have shown great activity and long-term remissions in poor-risk diffuse large B-cell lymphoma (DLBCL) when no other effective treatment options are available. Two CAR T-cell products [axicabtagene ciloleucel (axi-cel) and tisagenlecleucel] have obtained US Food and Drug Administration approval for the treatment of refractory DLBCL after two lines of therapy. A third product, liso-cel, is currently being evaluated in clinical trials and preliminary results appear very promising. CAR T-cell-related toxicity with cytokine-release syndrome and neurotoxicity remain important potential complications of this therapy. Here, we review the s biology, structure, clinical trial results and toxicity of two commercially approved CAR T-cell products and others currently being studied in multicenter clinical trials in B-cell NHLs.
  • 10.

    【2hr】The role of pembrolizumab in relapsed/refractory primary mediastinal large B-cell lymphoma

    包量

    机译 派姆单抗在复发/难治性原发性纵隔大B细胞淋巴瘤中的作用
    摘要：Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL). PMBCL comprises approximately 10% of DLBCLs, thus making it a rare variant of DLBCL. Cure rates for PMBCL with upfront regimens like DA-REPOCH exceed 90%. However, if there is a poor response to this first-line therapy, relapsed/refractory PMBCL (rrPMBCL) has limited treatment options. The historic trend is to treat rrPMBCL with salvage regimens commonly used for DLBCL followed by high-dose therapy and autologous stem cell transplant (HDT-ASCT); however, response rates to salvage therapy remain low and few patients are able to proceed to transplant. An interesting feature of PMBCL is that even though it is classified as a subtype of DLBCL, PMBCL actually shares many clinical, pathologic, and genetic features with classical Hodgkin lymphoma (cHL). For example, both frequently express program death ligand 1 and 2 (PD-L1/2), which is not seen in other mature B-cell lymphomas. The expression of PD-L1/2 in PMBCL makes PDL1 inhibitors, such as pembrolizumab, an attractive therapeutic target. Pembrolizumab is an effective and well-tolerated therapy now approved for a number of cancer types from advanced melanoma to relapsed/refractory cHL. There are now multi-institutional trials underway assessing the role of pembrolizumab in the treatment of rrPMBCL.
  • 11.

    【2hr】Optimal use of thrombopoietin receptor agonists in immune thrombocytopenia

    包量

    机译 血小板生成素受体激动剂在免疫性血小板减少症中的最佳使用
    摘要：The thrombopoietin receptor agonists (TPO-RAs) are a class of platelet growth factors commonly used to treat immune thrombocytopenia (ITP). There are three agents that have been investigated for the treatment of chronic ITP: the peptide agent romiplostim and the small molecule agents eltrombopag and avatrombopag. These agents offer a higher clinical response rate than most other ITP therapies but may require indefinite use. This review is a critical appraisal of the TPO-RAs in adult ITP, defining the optimal patient groups to receive these agents and assisting the hematologist with agent choice, goals of treatment, dosing strategies, and toxicity management. Use of endogenous thrombopoietin levels to predict response to eltrombopag and romiplostim treatment is discussed and alternative dosing protocols suited for certain patient subgroups are described. Finally, indications for discontinuation and combination therapy with other agents are considered.
  • 12.

    【2hr】Update on the role of venetoclax and rituximab in the treatment of relapsed or refractory CLL

    包量

    机译 Venetoclax和利妥昔单抗在治疗复发性或难治性CLL中的作用的最新进展
    摘要：For the treatment of mature B cell malignancies including chronic lymphocytic leukemia (CLL), the last 5 years has brought major advances in the application of targeted therapies. Whilst monoclonal anti-CD20 agents such as rituximab have a central role in combination with traditional cytotoxic therapy, their combination with novel agents that target the B cell receptor signaling pathway and other intracellular mechanisms of B cell proliferation is a new approach to treatment. Venetoclax is a highly specific novel agent inhibiting the bcl-2 anti-apoptotic pathway and has potent activity in CLL. Its combination with rituximab results in deeper and more durable responses and this regimen is a valuable option in the treatment of relapsed or refractory CLL including adverse prognostic variants such as cases that are fludarabine refractory or harbor the 17p chromosomal deletion. This review centers on the use of venetoclax and rituximab in relapsed or refractory CLL.
  • 13.

    【2hr】Immune targeting of the microenvironment in classical Hodgkin’s lymphoma: insights for the hematologist

    包量

    机译 免疫接种针对经典霍奇金淋巴瘤中的微环境：血液学家的见解
    摘要：While up to 80% of patients with Hodgkin’s lymphoma (HL) are cured with first-line therapy, relapsed/refractory (R/R) disease remains a clinical challenge and is fatal for many young patients. HL is unique in that the tumor cells (Hodgkin Reed–Sternberg; HRS cells) are a small fraction (<1%) of the tumor bulk, with the remaining tumor composed of the cells of the tumor microenvironment (TME). The support and integrity of the TME is necessary for HRS cell growth and survival. Targeting the programmed death 1 pathway has shown exciting activity in relapsed HL and led to United States Food and Drug Administration approval of the checkpoint inhibitors, nivolumab and pembrolizumab, for R/R HL. Novel combinations with checkpoint blockade therapy (CBT), targeted approaches such as combinations of CBT with brentuximab vedotin or chemotherapy, chimeric antigen receptor T-cells, and the use of CBT to potentially sensitize to subsequent therapy are being investigated as treatment approaches. As understanding of the HL TME grows, hopefully this will increase the number of rational therapeutic targets.
  • 14.

    【2hr】Management of myelodysplastic syndromes after failure of response to hypomethylating agents

    包量

    机译 对低甲基化药物反应失败后的骨髓增生异常综合征的管理
    摘要：Hypomethylating agents (HMAs) are the standard of care for patients with myelodysplastic syndrome (MDS). However, only around 50% of patients respond to these agents, and responses tend to be transient, with loss of response frequently happening within 2 years and being associated with very poor prognosis and limited therapeutic options. Identification of patients who will respond to HMAs is challenging. Mechanisms underlying resistance to HMAs are not clear yet. Recently, absence of response has been associated with increased cell-cycle quiescence among the hematopoietic progenitor cells. There are no standard-of-care options for patients after HMA failure. However, the increasing knowledge of MDS pathogenesis has led to the development of new potential therapies, including HMAs with longer half-life and exposure, inhibition of the antiapoptotic BCL2 protein with venetoclax or inhibition of immune-checkpoint regulatory proteins such as PD-1 or CTLA-4, innate immunity and targeting of CD33/CD3 with multiple monoclonal antibodies. In addition, multiple targeted agents are opening opportunities to treat subgroups of patients whose disease harbors mutations in TP53, IDH, FLT3, and genes involved in splicing machinery. Newer formulations of intensive chemotherapy and its different combinations may be considered a valid option in selected patients after HMA failure. Finally, decision making at the time of failure of response to HMAs should be personalized, taking into account that allogenic stem-cell transplantation remains the only therapeutic approach with curative potential in these patients. In the current review, we will focus on all the above aspects.
  • 15.

    【2hr】Novel monoclonal antibody-based treatment strategies in adults with acute lymphoblastic leukemia

    包量

    机译 成人急性淋巴细胞白血病基于单克隆抗体的新型治疗策略
    摘要：Adult acute lymphoblastic leukemia (ALL) has a poor overall survival compared with pediatric ALL where cure rates are observed in more than 90% of patients. The recent development of novel monoclonal antibodies targeting CD20, CD19, and CD22 has changed the long-term outcome of this disease, both in the frontline setting (e.g. rituximab) and for patients with relapsed/refractory disease (e.g. inotuzumab ozogamicin and blinatumomab). The CD3-CD19 bispecific T-cell-engaging antibody blinatumomab is also the first drug approved in ALL for patients with persistent or recurrent measurable residual disease, providing a new treatment paradigm for these patients. Several new agents are also in development that use novel constructs or target alternative surface epitopes such as CD123, CD25, and CD38. Herein, we review the role of monoclonal antibodies in adult ALL and summarize the current and future approaches in ALL, including novel combination therapies and the possibility of early incorporation of these agents into treatment regimens.
  • 16.

    【2hr】Current and emerging immunotherapeutic approaches to the treatment of multiple myeloma

    包量

    机译 当前和新兴的免疫治疗方法治疗多发性骨髓瘤
    摘要：Multiple myeloma (MM) has a worldwide incidence of 1–5/100,000/year. Outcomes have improved significantly in recent years following incorporation of immunomodulatory drugs and proteasome inhibitors into standard-of-care regimes. MM is profoundly immunosuppressive, enabling immune evasion, proliferation and disease progression. The role of the immune system in MM is becoming increasingly characterized and understood, and numerous therapies are under development or in routine clinical use targeting these elements of MM pathogenesis. In this review we discuss the immunosuppressive effects of MM, then the therapies targeting these defects. Specifically, we review the monoclonal and bispecific antibodies, alongside adoptive cellular therapies currently under investigation.
  • 17.

    【2hr】Chronic myelomonocytic leukemia associated with myeloid sarcomas and NPM1 mutation: a case report and literature review

    包量

    机译 慢性粒细胞性白血病伴髓样肉瘤和NPM1突变：病例报告和文献复习
    摘要：We present a case of chronic myelomonocytic leukemia (CMML) associated with myeloid sarcomas. The CMML also harbored a NPM1 mutation, which is uncommonly described outside the context of acute myeloid leukemia (AML). We describe our treatment strategy, which involved remission-induction chemotherapy that led to rapid resolution of myeloid sarcomas, and we present a literature review highlighting the treatment challenges that similar cases pose.
  • 18.

    【2hr】Efficacy and safety of simoctocog alfa (Nuwiq®) in patients with severe hemophilia A: a review of clinical trial data from the GENA program

    包量

    机译 辛法考克阿尔法（Nuwiq®）在严重血友病A中的疗效和安全性：GENA计划的临床试验数据回顾
    摘要：Simoctocog alfa (human-cl rhFVIII, Nuwiq®) is a 4th generation recombinant FVIII (rFVIII), without chemical modification or fusion with any other protein/fragment. Nuwiq® is produced in a human embryonic kidney cell line (HEK293F), which ensures human-specific post-translational protein processing. Nuwiq® was evaluated in seven prospective clinical studies in 201 adult and pediatric previously treated patients (PTPs) with severe hemophilia A. The NuProtect study in 110 previously untreated patients (PUPs) is ongoing. The mean half-life of Nuwiq® was 15.1–17.1 h in PTP studies with adults and adolescents, and 12.5 h in children aged 2–12 years. Clinical trials in PTPs demonstrated the efficacy and safety of Nuwiq® in the prevention and treatment of bleeds and as surgical prophylaxis. In the NuPreviq study of pharmacokinetic (PK)-guided personalized prophylaxis in 66 adult PTPs, 83% of patients had no spontaneous bleeds during 6 months of personalized prophylaxis and 57% were treated ⩽2 per week. No FVIII inhibitors were detected in PTPs after treatment with 43,267 injections and >80 million IU of Nuwiq®. Interim data for 66 PUPs with ⩾20 exposure days to Nuwiq® in NuProtect demonstrated a low cumulative high-titer inhibitor rate of 12.8% [actual incidence 12.1% (8/66)] and convincing efficacy and safety.
  • 19.

    【2hr】Management of perioperative hemostasis in a severe hemophilia A patient with inhibitors on emicizumab using global hemostasis assays

    包量

    机译 重度血友病围手术期止血的管理使用整体止血分析的阿米单抗抑制剂患者
    摘要：Background:Patients with severe hemophilia A and inhibitors are at risk of bleeding during invasive procedures. The standard of care for preventing perioperative bleeding has been replacement therapy with FVIII concentrates or for patients with high-titer inhibitors, bypassing agents. However, there is no consensus on the appropriate management of surgery in patients receiving the novel agent emicizumab. The aim of this study was to demonstrate a case of a patient on emicizumab undergoing major surgery with bypassing agents with preoperative use of the thrombin generation assay (TGA) and thromboelastography (TEG).
  • 20.

    【2hr】Novel therapy in Acute myeloid leukemia (AML): moving toward targetedapproaches

    包量

    机译 急性髓细胞性白血病（AML）的新疗法：朝着目标化方向发展方法
    摘要：Acute myeloid leukemia (AML) is a heterogenous and complex disease characterized by rapid cellular proliferation, an aggressive clinical course, and generally high mortality. While progress has been made in the understanding of the genetic and molecular biology of the disease, the standard of care for patients had only changed minimally over the past 40 years. Recently, rapid movement of potentially useful agents from bench to bedside has translated into new therapies either recently approved or in clinical trials. These therapies include improved chemotherapies, mutationally targeted inhibitors, pro-apoptotic agents, microenvironment targeting molecules, cell cycle checkpoint inhibitors, and epigenetic regulators. Furthermore, advances in immunotherapy employ monoclonal and bispecific antibodies, chimeric antigen receptor (CAR) T cells, checkpoint inhibitors, and vaccines provide an alternative pathway for AML treatment. In this review, we discuss the recent results of completed or ongoing clinical trials with these novel therapeutic agents in AML.
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