BTK抑制剂在中枢神经系统淋巴瘤中的治疗作用及安全性分析

目的：研究布鲁顿酪氨酸激酶（Bruton’s tyrosine kinase,BTK）抑制剂治疗复发/难治性中枢神经系统淋巴瘤(relapsed/refractory central nervous system lymphoma,R/R CNSL）的有效性和安全性。方法：回顾性分析郑州大学第一附属医院2018年10月至2021年10月收治的43例R/R CNSL患者,分别使用BTK抑制剂单药、BTK抑制剂联合化疗、BTK抑制剂联合免疫治疗方案,BTK抑制剂包括伊布替尼、泽布替尼、奥布替尼,初始剂量分别为（420～560）mg/d、320 mg/d、（100～150）mg/d,分析治疗后的最好疗效和不良反应。结果：BTK抑制剂单药组（A组）、BTK抑制剂联合化疗组（B组）、BTK抑制剂联合免疫治疗组（C组）的客观缓解率（objective response rate,ORR）分别为44.4%、85.7%和76.9%,B组的ORR高于A、C组,原发中枢神经系统淋巴瘤（primary CNSL,PCNSL）患者的ORR(78.6%vs. 66.7%)高于继发中枢神经系统淋巴瘤（second...     

伊布替尼治疗套细胞淋巴瘤临床研究进展

摘 要：套细胞淋巴瘤是一种少见的B细胞非霍奇金淋巴瘤类型,兼有惰性淋巴瘤和侵袭性淋巴瘤的临床病理特点,治疗上以全身化疗及造血干细胞移植为主。伊布替尼是全球第一个上市的布鲁顿氏酪氨酸激酶（Bruton′s tyrosine kinase,BTK）抑制剂,主要通过抑制BTK信号通路,来达到细胞增殖、凋亡及细胞运动的调节。全文就伊布替尼治疗套细胞淋巴瘤临床研究进展作一分析。     

伊布替尼的常见不良反应及临床应对策略

伊布替尼作为第一代布鲁顿酪氨酸激酶(Bruton's tyrosine kinase，BTK)抑制剂，为治疗慢性淋巴细胞白血病/小淋巴细胞淋巴瘤(chronic lymphocytic leukemia/small lymphocytic lymphoma，CLL/SLL)、复发的套细胞淋巴瘤(mantle cell lymphoma，MCL)等在内的B细胞淋巴瘤有效率高、安全性好的口服小分子靶向药物。自伊布替尼在国内上市以来，越来越多的中国患者从中获益，但随着使用例数增多和时间延长，临床上面临着更多与既往化疗药物相比出现的特殊不良反应，如出血、房颤、腹泻和关节痛等。因伊布替尼作用机制的独特性，在处理不良反应时亦需关注药物相互作用。本文总结相关文献中伊布替尼不良反应的处理策略，旨在为临床提供参考。      

B细胞受体通路抑制剂在慢性淋巴细胞白血病治疗中的研究进展：第57届美国血液学会年会报道

随着Bruton酪氨酸激酶（BTK）抑制剂依鲁替尼（ibrutinib）及磷脂酰肌醇-3-激酶（PI3K）抑制剂idelalisib在复发／难治非霍奇金淋巴瘤（NHL）治疗中的成功,一系列新的B细胞受体（BCR）通路抑制剂也逐步进入临床试验。第57届美国血液学会（ASH）年会继续对依鲁替尼和idelalisib单药或联合用药治疗慢性淋巴细胞白血病（CLL）的探索保持了高度热情。另外脾酪氨酸激酶（SYK）抑制剂及新的BTK和PI3K抑制剂也崭露头角,为改善依鲁替尼和idelalisib耐药患者的疗效提供了新的选择。文章就第57届ASH年会中关于BCR通路抑制剂治疗CLL的进展进行介绍。     

BTK抑制剂治疗慢性淋巴细胞白血病导致痛风反复发作1例

<正>慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（chronic lymphocytic leukemia/small lymphocytic lymphoma,CLL/SLL）是一类具有特定免疫表型特征的成熟B淋巴细胞克隆增殖性疾病,以淋巴细胞在外周血、骨髓、脾脏或淋巴结聚集为特征[1]。布鲁顿酪氨酸激酶（bruton tyrosine kinase inhibitor,BTK）抑制剂是目前许多CLL患者的一线治疗选择,可以显著改善预后[2]。国内目前使用的BTK抑制剂主要包括伊布替尼、泽布替尼等,常见不良反应有腹泻、出血、高血压、房颤等,     

Bruton酪氨酸激酶抑制剂在套细胞淋巴瘤中的研究进展

套细胞淋巴瘤（MCL）是一种高度异质性的疾病,其临床表现多种多样,对常规化疗药物多不敏感,预后相对较差。以依鲁替尼（ibrutinib）为代表的新型Bruton酪氨酸激酶（BTK）靶向药物的出现为MCL的治疗提供了新希望。文章就BTK抑制剂在MCL治疗中的最新研究进展进行综述。     

布鲁顿酪氨酸激酶抑制剂在B 细胞淋巴瘤中的研究进展*

B 细胞受体（B -cell receptor,BCR ）信号通路在B 细胞肿瘤的发生、发展中起关键作用,其慢性持续的激活状态使正常细胞具备转化为恶性肿瘤细胞的能力。布鲁顿酪氨酸激酶（bruton tyrosine kinase ,BTK ）是非受体型酪氨酸激酶TEC 家族的一员,在BCR 信号通路的活化过程中起着关键的作用。通过BTK 小分子抑制剂调控BCR 信号转导,已经成为治疗某些B 细胞淋巴瘤的新靶点,并为B 细胞非霍奇金淋巴瘤（B-cell non-Hodgkin's lymphoma,B-NHL）的治疗带来新突破。本文将对现有BTK 小分子抑制剂在临床上的应用现状作一综述。      

新型ALK抑制剂在晚期非小细胞肺癌治疗中的研究进展

克唑替尼作为第一代间变性淋巴瘤激酶(ALK)抑制剂,对于治疗ALK阳性晚期非小细胞肺癌疗效显著,但耐药问题限制了其临床应用.二代ALK抑制剂色瑞替尼和艾乐替尼等也相继被美国食品药品监督管理局(FDA)批准上市,而更多安全有效的新型ALK抑制剂正处于研发阶段.本文就新型ALK抑制剂的研究进展作一系统性综述,以期为新型ALK抑制剂的临床应用提供选择依据.     

ALK基因抑制剂治疗非小细胞肺癌脑转移的研究进展

间变性淋巴瘤激酶(ALK)重排是非小细胞肺癌(NSCLC)强有力的致癌驱动基因之一,伴ALK重排的NSCLC患者应用第一代ALK抑制剂如克唑替尼的治疗疗效要远远优于化疗.同时越来越多的研究报道了ALK抑制剂在伴有脑转移的NSCLC患者中的颅内有效率.然而尽管第一代ALK抑制剂治疗ALK阳性NSCLC脑转移有初步的临床数据,但在获得性耐药后,肿瘤出现不同程度的复发,给肿瘤患者的后续治疗带来新的挑战.新一代ALK抑制剂如艾乐替尼、色瑞替尼、AP26113和PF-06463922的相继出现解决了这一问题.     

老年套细胞淋巴瘤患者的治疗进展

套细胞淋巴瘤（MCL）是一种小B细胞非霍奇金淋巴瘤,好发于中老年人群。对于老年患者,利妥昔单抗+环磷酰胺+多柔比星+长春新碱+泼尼松（R-CHOP）方案、苯达莫司汀+利妥昔单抗（BR）方案、伊布替尼+利妥昔单抗（IR）方案及包含减量阿糖胞苷的方案都有较好的疗效和安全性。近年来,蛋白酶体抑制剂、Bruton酪氨酸激酶（BTK）抑制剂、B细胞淋巴瘤/白血病-2(Bcl-2)抑制剂和免疫调节剂纳入到老年MCL患者的治疗方案中,磷脂酰肌醇-3-激酶（PI3K）抑制剂、嵌合抗原受体T细胞疗法（CAR-T）的应用为复发难治性MCL患者提供了新的治疗选择。本文对老年MCL患者的治疗进展进行综述。     

US Food and Drug Administration approvals for Bruton tyrosine kinase inhibitors in patients with chronic lymphocytic leukemia: Potential inefficiencies in trial design and evidence generation

The US Food and Drug Administration granted acalabrutinib approval as the second Bruton tyrosine kinase (BTK) inhibitor to treat patients with chronic lymphocytic leukemia and small lymphocytic lymphoma as monotherapy or in combination with obinutuzumab. This approval was based on 2 phase 3 trials: ELEVATE-TN and ASCEND. There are several concerns with the design of these trials, including suboptimal treatment of patients in the control arm, expansion of the trial population, and lack of data regarding efficacy or tolerability compared with ibrutinib, a first-in-class drug. The Food and Drug Administration approval of acalabrutinib for patients with chronic lymphocytic leukemia and small lymphocytic lymphoma represents concerning drug approval patterns in the United States and a weakness in evidence generation.     

Bruton’s Tyrosine Kinase (BTK) Inhibitors in Clinical Trials

BTK is a cytoplasmic, non-receptor tyrosine kinase that transmits signals from a variety of cell-surface molecules, including the B-cell receptor (BCR) and tissue homing receptors. Genetic BTK deletion causes B-cell immunodeficiency in humans and mice, making this kinase an attractive therapeutic target for B-cell disorders. The BTK inhibitor ibrutinib (PCI-32765, brand name: Imbruvica) demonstrated high clinical activity in B-cell malignancies, especially in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenstrom's macroglobulinemia (WM). Therefore, ibrutinib was granted a ‘breakthrough therapy’ designation for these indications and was recently approved for the treatment of relapsed MCL by the U.S. Food and Drug Administration. Other BTK inhibitors in earlier clinical development include CC-292 (AVL-292), and ONO-4059. In CLL and MCL, ibrutinib characteristically induces redistribution of malignant B cells from tissue sites into the peripheral blood, along with rapid resolution of enlarged lymph nodes and a surge in lymphocytosis. With continuous ibrutinib therapy, growth- and survival-inhibitory activities of ibrutinib result in the normalization of lymphocyte counts and remissions in a majority of patients. This review discusses the clinical advances with BTK inhibitor therapy, as well as its pathophysiological basis, and outlines perspectives for future use of BTK inhibitors.     

维奈克拉治疗恶性血液病临床应用指导原则（2021年版）

维奈克拉是全球首个具有高亲和性靶向肿瘤细胞凋亡独特作用机制的口服bcl-2抑制剂,在血液系统肿瘤中具有广阔的应用前景。2020年底维奈克拉在我国获批上市,为急性髓系白血病（AML）患者带来了新希望。但目前临床医生对维奈克拉的用药经验较少,尚缺乏对其临床规范应用和患者管理的相关共识。基于维奈克拉应用现状,结合国外最新的权威指南及循证医学证据,制定了维奈克拉治疗恶性血液病的临床应用指导原则,包括应用于AML、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤的临床管理。     

Selective BTK inhibition improves bendamustine therapy response and normalizes immune effector functions in chronic lymphocytic leukemia

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been shown to be highly effective in patients with chronic lymphocytic leukemia (CLL) and is approved for CLL treatment. Unfortunately, resistance and intolerance to ibrutinib has been observed in several studies, opening the door for more specific BTK inhibitors. CC-292 (spebrutinib) is a BTK inhibitor with increased specificity for BTK and less inhibition of other kinases. Our in vitro studies showed that CC-292 potently inhibited B-cell receptor signaling, activation, proliferation and chemotaxis of CLL cells. In in vivo studies using the adoptive transfer TCL1 mouse model of CLL, CC-292 reduced tumor load and normalized tumor-associated expansion of T cells and monocytes, while not affecting T cell function. Importantly, the combination of CC-292 and bendamustine impaired CLL cell proliferation in vivo and enhanced the control of CLL progression. Our results demonstrate that CC-292 is a specific BTK inhibitor with promising performance in combination with bendamustine in CLL. Further clinical trials are warranted to investigate the therapeutic efficacy of this combination regimen.     

Treatment algorithm for Japanese patients with chronic lymphocytic leukemia in the era of novel targeted therapies

Treatment for patients with chronic lymphocytic leukemia (CLL) is becoming more individualized due to the recent introduction of novel molecularly targeted therapies into the therapeutic armamentarium. Genomic and molecular risk factors in CLL patients determine the individual risk for disease progression and response to therapy, and can impact survival. In this review article, we discuss current treatment strategies for CLL patients in Japan, where the novel targeted agents, the BTK inhibitor ibrutinib and BCL2 antagonist venetoclax, now are available and increasingly used in clinical practice. We also discuss the importance of CLL risk factors for making therapy decisions, focusing on immunoglobulin variable region heavy chain (IGHV) mutation status, 11q deletion, and 17p deletion. Treatment approaches for CLL have rapidly changed in the past few years because of these new targeted agents. They are highly effective, well tolerated, and have been demonstrated in a series of large randomized clinical trials to improve survival when compared with conventional chemotherapy-based treatment. Therefore, for most patients, especially high-risk CLL patients, BTK inhibitor and BCL2 antagonist therapies are preferred over chemo-immunotherapy. Currently ongoing studies seek to determine the best sequence for these new agents and whether a combination therapy approach is beneficial. With these developments, a new era of chemotherapy-free treatment for CLL patients is expected.     

316例淋巴组织肿瘤骨髓细胞形态学的WHO分型观察

目的：观察淋巴系肿瘤在骨髓细胞形态学中的表现,探讨WHO分型有关问题。方法：采用WHO分型方法,对316例伴有骨髓细胞形态学表现异常的淋巴组织肿瘤进行分析。结果：前体B、T淋巴母细胞急性白血病(ALL)占46．6％,外周B淋巴组织肿瘤中慢性淋巴细胞白血病/小淋巴细胞淋巴瘤(CLL／SLL)占18．4％,多发性骨髓瘤(MM)占14．6％,其他恶性淋巴瘤细胞骨髓浸润亦较多见,占12．2％,浸润程度不一。其余比例较少的疾病为Burkitt淋巴瘤／白血病、毛细胞白血病(HCL)、幼稚淋巴细胞白血病(PLL)、浆细胞白血病(PCL)、伴有绒毛淋巴细胞的脾淋巴瘤(SLVL)。B淋巴系肿瘤病例较T淋巴组织肿瘤明显增多。结论：WHO分型以细胞形态学和免疫分型为基础,确定主要分化类型和分化程度,并结合细胞遗传学异常以及特殊的病因学和临床特点综合分类,可能是目前国际上最为合理的分类法。     

CD5+ true SLL/CLL with plasmacytic differentiation and an unusual 1p36 translocation: case report and review of the literature

Lymphoplasmacytic lymphoma (LPL) and small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL)are distinct clinicopathologic entities. Although some cases of SLL/CLL may show plasmacytic differentiation and be associated with monoclonal immunoglobulin in serum, such cases appear to be very rare, and if plasma cell differentiation were marked, differentiation of SLL/CLL from LPL could be difficult. We report a rare case of true CD5-positive small lymphocytic lymphoma/chronic lymphocytic leukemia with unequivocal plasmacytic differentiation. This case also showed an abnormality of chromosome 1p36 not previously described in small lymphocytic lymphoma/chronic lymphocytic leukemia.     

SOHO State of the Art Updates and Next Questions: Targeted therapies and emerging novel treatment approaches for Waldenström Macroglobulinemia

Waldenström Macroglobulinemia (WM) is a rare hematologic malignancy characterized by the presence of lymphoplasmacytic lymphoma cells involving the bone marrow and production of a monoclonal IgM paraprotein. Recurrent somatic mutations in MYD88^L265P and CXCR4 have been reported in 90% to 95% and 30% to 40% of patients with WM, respectively. Standard treatment regimens combine the anti-CD20 antibody rituximab with alkylating agents (eg, bendamustine, cyclophosphamide), nucleoside analogs (eg, fludarabine, cladribine), or proteasome inhibitors (eg, bortezomib, carfilzomib, and ixazomib). Covalent BTK inhibitors (eg, ibrutinib, acalabrutinib, zanubrutinib) have shown to be safe and highly effective in patients with WM. Novel and promising agents in this disease include next-generation covalent BTK inhibitors (eg, tirabrutinib, orelabrutinib), non-covalent BTK inhibitors (eg, pirtobrutinib, ARQ531), BCL-2 antagonists (eg, venetoclax), and CXCR4-targeted agents (eg, mavorixafor, ulocuplumab), among others. Future studies will focus on developing fixed-duration combinations regimens with these novel agents aimed at increasing durable responses while minimizing toxicity and cost.