R-BAP联合BTK抑制剂方案对初治套细胞淋巴瘤患者的疗效和安全性分析

目的：探讨以利妥昔单抗、苯达莫司汀、阿糖胞苷和泼尼松联合布鲁顿氏酪氨酸激酶（Bruton’s tyrosine kinase,BTK）抑制剂的方案治疗MCL患者的疗效和安全性,旨在改良套细胞淋巴瘤（mantle cell lymphoma,MCL）的治疗方案。方法：回顾性分析郑州大学第一附属医院2021年3月至2023年11月收治的26例初治MCL病例,采用利妥昔单抗、苯达莫司汀、阿糖胞苷和泼尼松联合BTK抑制剂治疗方案的疗效和不良反应。结果：26例初治MCL患者中位年龄为59(41～72)岁,其中男性22例、女性4例,中位随访时间为12(3～28)个月。在26例患者中,总缓解率（overall response rate,ORR）为92.3%,完全缓解率（complete response rate,CRR）为88.5%。中位无进展生存期（progression-free survival,PFS）和中位总生存期（overall survival,OS）均未达到,1年PFS率为81.25%,1年OS率为92.3%。MCL国际预后指数（MIPI）评分0～3分组的PFS优于MIPI评分4...     

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。     

32例套细胞淋巴瘤中BTK蛋白的表达及临床意义

  目的  检测套细胞淋巴瘤(mantle cell lymphoma,MCL)患者病理组织中Bruton酪氨酸激酶(Bruton tyrosin kinase,BTK)表达水平并分析其与患者临床特征及预后的相关性。  方法  选取天津医科大学肿瘤医院2011年1月至2015年12月期间经病理检测诊断为MCL且随访资料完整的32例患者和10例良性淋巴结增生患者的病理组织。采用免疫组织化学法对32例MCL组织和10例良性淋巴结组织染色,并采用SPSS 17.0统计学软件对所收集的患者临床数据资料进行分析。  结果  BTK蛋白在MCL组织和正常的淋巴组织中均呈阳性表达,但在MCL病理组织中多为强阳性表达;BTK阳性表达与Ki-67和MIPI评分相关;应用Kaplan-Meier法对预后进行分析,显示BTK强阳性表达患者的无进展生存期(progression free survival,PFS)显著低于BTK弱表达患者(P=0.030),但总生存期(overall survival,OS)无统计学意义(P=0.073);PFS的单因素分析结果显示,年龄≥65岁,ECOG评分≥2分,骨髓受累,BTK强阳性表达,Ki-67＞30%,根据套细胞淋巴瘤国际预后指数(mantle cell lymphoma international prognostic index,MIPI)评分≥6分,皆是MCL患者的不良预后因素,但在Cox多因素分析结果中仅MIPI评分≥6分可作为MCL患者的独立不良预后因素。  结论  BTK在MCL患者中多为强阳性表达,且与Ki-67和MIPI评分呈正相关;BTK强阳性表达患者的PFS显著低于BTK弱表达患者,但由于随访时间短暂和样本量限制,BTK的强阳性表达尚不能作为PFS的一项独立不良预后因素。      

硼替佐米治疗套细胞淋巴瘤的分子学机制

 套细胞淋巴瘤（MCL）是生存期最短的非霍奇金淋巴瘤（NHL）,目前尚不能根治。硼替佐米是第一个用于治疗血液系统恶性肿瘤的蛋白酶体抑制剂,主要用于多发性骨髓瘤（MM）及复发难治性MCL的治疗。探讨硼替佐米治疗MCL的相关机制,其中包括调节细胞周期、影响细胞凋亡、干扰MCL的微环境以及与其他抗肿瘤药物的协同作用等,有助于未来合理应用硼替佐米治疗MCL。     

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...     

替西罗莫司治疗套细胞淋巴瘤的研究进展

套细胞淋巴瘤（MCL）是一种少见、独特的B细胞非霍奇金淋巴瘤（NHL）亚型.现有不少治疗MCL的药物和方案,均有一定疗效,但疗效维持时间短,不够理想.目前认为MCL是难以治愈的,预后不良.文章着重介绍了一种治疗MCL的新药替西罗莫司.该药是雷帕霉素的衍生物,它通过下调淋巴瘤的Cyclin D1和Ki-67,阻断细胞周期,诱导肿瘤缩小,抑制肿瘤生长.研究显示替西罗莫司能诱导MCL患者缓解和延长生存,特别对复发性或难治性MCL患者有一定疗效.另外,替西罗莫司与利妥昔单抗,或与其他化疗药物联合应用,能获得比单用替西罗莫司更好的效果.     

靶向药物治疗套细胞淋巴瘤的研究进展

套细胞淋巴瘤(MCL)是一种少见的非霍奇金淋巴瘤亚型.MCL临床表现有两种类型:一种为惰性表现,病情进展缓慢;另一种为侵袭性表现,病程进展迅速.近年,一些用于MCL治疗的新靶向药物已经问世.这些靶向药物较常规化疗提高了对复发/难治性MCL的疗效,其治疗MCL的靶点为B细胞淋巴瘤表面抗原、B细胞受体信号和肿瘤细胞微环境等.文章介绍了MCL靶向药物的研究进展.     

套细胞淋巴瘤诊治进展

套细胞淋巴瘤（MCL）是小 B 细胞淋巴瘤中一组高侵袭性的非霍奇金淋巴瘤（NHL）,约占NHL 的6%。MCL 起病隐匿、侵袭性强、恶性程度高、预后差,因此,MCL 的诊断及鉴别诊断至关重要。另外,MCL 分子病理模型、细胞周期蛋白 D1阴性 MCL、MCL 分期预后及分层治疗选择均值得关注。     

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。      

套细胞淋巴瘤研究进展：第55届美国血液学会年会报道

套细胞淋巴瘤（MCL）是一种高度侵袭性的非霍奇金淋巴瘤,常可累及淋巴结、胃肠道、骨髓等,易出现治疗耐药和疾病进展.第55届美国血液学会年会关于MCL的研究报告涵盖了多个方面：基础研究方面,ATM、POT1等新型突变的发现以及肿瘤微环境机制的提出进一步完善了MCL发病机制;预后指标方面,基于分子技术的微小残留病灶检测及全基因组甲基化分析等手段为MCL预后和疗效监测提供了新的工具,实现分层治疗;来那度胺、苯达莫司汀、利妥昔单抗及自体造血干细胞移植等的合理使用为MCL老年患者的治疗提供了新方向,ibrutinib、ABT-199及MLN8237等新型药物在初期临床试验显示出令人鼓舞的结果,为MCL治疗提供了新的希望.     

Bruton tyrosine kinase is commonly overexpressed in mantle cell lymphoma and its attenuation by Ibrutinib induces apoptosis

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that characteristically shows overexpression of cyclin-D1 due to an alteration in the t(11;14)(q13;q32) chromosomal region. Although there are some promising treatment modalities, great majority of patients with this disease remain incurable. The B-cell antigen receptor (BCR) signaling plays a crucial role in B-cell biology and lymphomagenesis. Bruton tyrosine kinase (BTK) has been identified as a key component of the BCR signaling pathway. Evidence suggests that the blockade of BTK activity by potent pharmacologic inhibitors attenuates BCR signaling and induces cell death. Notably, the expression levels and the role of BTK in MCL survival are still elusive. Here, we demonstrated a moderate to strong BTK expression in all MCL cases (n = 19) compared to benign lymphoid tissues. Treatment of MCL cell lines (Mino or Jeko-1) with a potent BTK pharmacologic inhibitor, Ibrutinib, decreased phospho-BTK-Tyr²²³ expression. Consistent with this observation, Ibrutinib inhibited the viability of both Mino and JeKo-1 cells in concentration- and time-dependent manners. Ibrutinib also induced a concentration-dependent apoptosis in both cell lines. Consistently, Ibrutinib treatment decreased the levels of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1 protein. These findings suggest that BTK signaling plays a critical role in MCL cell survival, and the targeting of BTK could represent a promising therapeutic modality for aggressive lymphoma     

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.     

Inhibitors of BCR signalling interrupt the survival signal mediated by the micro‐environment in mantle cell lymphoma

Several studies provide evidences for mantle cell lymphoma (MCL) cell survival relying on B‐cell receptor (BCR)‐mediated signalling pathways, whereas the nature of this activation is unknown. Significant progress in MCL treatment is achieved through therapies targeting BCR‐associated kinases, i.e., Ibrutinib and Fostamatinib, inhibitors of BTK and SYK, respectively. Our study addresses survival signals emanating from the BCR or the tumour environment and how inhibiting BCR signalling effectors might impact these survival signals. We found that BTK was constitutively activated and that SYK phosphorylation was highly increased and sustained upon BCR activation of primary MCL cells. Moreover, MCL cells from leukaemic patients secreted high amount of IL‐1β, IL‐6, IL‐8 and CCL5. Activation of the BCR induced (i) cell survival, (ii) STAT3 activation and (iii) increased autocrine secretion of IL‐1β, IL‐6, IL‐8, CCL5, IL‐10, TNFα and VEGF. Specific inhibition of BTK by Ibrutinib or SYK by Fostamatinib (R406) reversed these protective effects and decreased both basal and BCR‐induced autocrine cytokine secretions associated with STAT3 phosphorylation. Interestingly, targeting BTK and SYK prevented and inhibited BCR‐induced MCL cell adhesion to human bone marrow stromal cells (HMSCs) in short‐ and long‐term co‐culture. We demonstrated that BCR‐induced survival relies on autocrine secretion of IL‐1β, TNFα and CCL5 that might facilitate adhesion of MCL cells to HMSC. Treatment with Ibrutinib or Fostamatinib blocked the chemotactic signal thus increasing apoptosis.     

Treatment Landscape of Relapsed/Refractory Mantle Cell Lymphoma: An Updated Review

Mantle cell lymphoma (MCL) accounts for nearly 2-6% of all non-Hodgkin lymphoma (NHL) cases, with a steady incidence increase over the past few decades. Although many patients achieve an adequate response to the upfront treatment, the short duration of remission with rapid relapse is challenging during MCL management. In this regard, there is no consensus on the best treatment options for relapsed/refractory (R/R) disease, and the international guidelines demonstrate wide variations in the recommended approaches. The last decade has witnessed the introduction of new agents in the treatment landscape of R/R MCL. Since the introduction of Bruton's tyrosine kinase (BTK) inhibitors, the treatment algorithm and response of R/R MCL patients have dramatically changed. Nevertheless, BTK resistance is common, necessitating further investigations to develop novel agents with a more durable response. Novel agents targeting the B-cell receptor (BCR) signaling have exhibited clinical activity and a well-tolerable safety profile. However, as the responses to these novel agents are still modest in most clinical trials, combination strategies were investigated in pre-clinical and early clinical settings to determine whether the combination of novel agents would exhibit a better durable response than single agents. In this report, we provide an updated literature review that covers recent clinical data about the safety and efficacy of novel therapies for the management of R/R MCL.     

SOHO State of the Art Updates and Next Questions: Managing Relapsed Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma i.e., incurable with current therapies. While some patients experience prolonged remissions following initial therapy, most will have a relapsing-remitting course requiring several lines of treatment over the course of their disease. Several targeted therapies are now available to treat patients with relapsed MCL. The Bruton's tyrosine kinase (BTK) inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib, are highly active in MCL and currently approved for treating patients with relapsed disease. Bortezomib and lenalidomide are available as monotherapy or in combination with other agents. Venetoclax is active and can be considered for use in relapsed MCL, although it is not currently approved by regulatory agencies. Chimeric antigen receptor T-cell (CAR-T) therapy with brexucabtagene autoleucel yields high response rates and is now approved for patients with relapsed MCL. Allogeneic stem cell transplant remains an option for a small subset of medically fit and motivated patients who have progressed through multiple lines of therapy, although its use is limited by substantial toxicity. There is currently no standard approach to sequencing therapies for patients with relapsed MCL, and the ability to utilize disease biologic and clinical characteristics to guide treatment decisions in this setting remains limited. In this review, we summarize the current evidence to guide the management of patients with relapsed MCL, review emerging agents and combination therapies that are under investigation, and outline our current treatment approach for these patients.     

The mTOR kinase inhibitor everolimus synergistically enhances the anti‐tumor effect of the Bruton's tyrosine kinase (BTK) inhibitor PLS‐123 on Mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive and incurable malignant disease. Despite of general chemotherapy, relapse and mortality are common, highlighting the need for the development of novel targeted drugs or combination of therapeutic regimens. Recently, several drugs that target the B‐cell receptor (BCR) signaling pathway, especially the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicate that pharmacological inhibition of BCR pathway holds promise in MCL treatment. Here, we have developed a novel irreversible BTK inhibitor, PLS‐123, that has more potent and selective anti‐tumor activity than ibrutinib in vitro and in vivo. Using in vitro screening, we discovered that the combination of PLS‐123 and the mammalian target of rapamycin (mTOR) inhibitor everolimus exert synergistic activity in attenuating proliferation and motility of MCL cell lines. Simultaneous inhibition of BTK and mTOR resulted in marked induction of apoptosis and cell cycle arrest in the G1 phase, which were accompanied by upregulation of pro‐apoptotic proteins (cleaved Caspase‐3, cleaved PARP and Bax), repression of anti‐apoptotic proteins (Mcl‐1, Bcl‐xl and XIAP), and downregulation of regulators of the G1/S phase transition (CDK2, CDK4, CDK6 and Cyclin D1). Gene expression profile analysis revealed simultaneous treatment with these agents led to inhibition of the JAK2/STAT3, AKT/mTOR signaling pathways and SGK1 expression. Finally, the anti‐tumor and pro‐apoptotic activities of combination strategy have also been demonstrated using xenograft mice models. Taken together, simultaneous suppression of BTK and mTOR may be indicated as a potential therapeutic modality for the treatment of MCL.     

Combining Ibrutinib with Chk1 Inhibitors Synergistically Targets Mantle Cell Lymphoma Cell Lines

Background

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with an unfavorable clinical course. Besides deregulation of the cell cycle, B cell receptor (BCR) signaling, essential for MCL proliferation and survival, is also often deregulated due to constitutive activation of Bruton’s tyrosine kinase (BTK). The BTK inhibitor ibrutinib has been approved as a therapy for refractory MCL, and while it shows some clinical activity, patients frequently develop primary or secondary ibrutinib resistance and have very poor outcomes after relapsing following ibrutinib treatment.

Objective

To overcome ibrutinib resistance, new therapeutic approaches are needed. As checkpoint kinase 1 (Chk1) inhibitors have recently been shown to be effective as single agents in MCL, we assessed the combination of ibrutinib with Chk1 inhibitors.

Methods

We examined the activity of ibrutinib combined with the Chk1 inhibitor PF-00477736 in eight MCL cell lines and analyzed underlying cellular and molecular effects.

Results

The combination was synergistic in all tested cell lines through different mechanisms. The treatment induced apoptosis in ibrutinib-sensitive cell lines, while in ibrutinib-resistant cells the effect was mainly cytostatic and occurred at micromolar concentrations of ibrutinib.

Conclusions

The pharmacological approach of simultaneously targeting cell cycle checkpoints (by Chk1 inhibitors) and pro-survival pathways (by ibrutinib) might offer a promising new therapeutic strategy for MCL patients.

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Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma

The aggressive biological behavior of mantle cell lymphoma (MCL) and its short response to current treatment highlight a great need for better rational therapy. Herein, we investigate the ability of ABT-199, the Bcl-2-selective BH3 mimetic, to kill MCL cells. Among MCL cell lines tested (n = 8), only three were sensitive (LD₅₀ < 200 nM). In contrast, all primary MCL samples tested (n = 11) were highly sensitive to ABT-199 (LD₅₀ < 10 nM). Mcl-1 and Bcl-x_L both confer resistance to ABT-199-specific killing and BCL2/(BCLXL + MCL1) mRNA ratio is a strong predictor of sensitivity. By mimicking the microenvironment through CD40 stimulation, we show that ABT-199 sensitivity is impaired through activation of NF-kB pathway and Bcl-x_L up-regulation. We further demonstrate that resistance is rapidly lost when MCL cells detach from CD40L-expressing fibroblasts. It has been reported that ibrutinib induces lymphocytosis in vivo holding off malignant cells from their protective microenvironment. We show here for two patients undergoing ibrutinib therapy that mobilized MCL cells are highly sensitive to ABT-199. These results provide evidence that in situ ABT-199 resistance can be overcome when MCL cells escape from the lymph nodes. Altogether, our data support the clinical application of ABT-199 therapy both as a single agent and in sequential combination with BTK inhibitors.