Four‐year follow‐up of a single arm,phase II clinical trial of ibrutinib with rituximab (IR) in patients with relapsed/refractory mantle cell lymphoma (MCL)

Ibrutinib has shown significant activity in patients with relapsed or refractory mantle cell lymphoma (RR‐MCL). We report the long‐term outcome and safety profile of a single‐centre, single arm, open‐label, phase 2 study of RR‐MCL treated with IR. Overall, the median follow‐up time was 47 months (range 1–52 months), median duration on treatment was 16 months (range 1–53 months) and median number of treatment cycles was 17 (range 1–56). Twenty‐nine patients (58%) achieved complete remission and of these, 12 patients continue on study. Thirty‐eight patients discontinued treatment, 14 due to disease progression (2 transformed). Patients with blastoid morphology, high risk MCL International Prognostic Index score and high Ki67% had inferior survival. The commonest grade 1–2 toxicities were fatigue, diarrhoea, nausea, arthralgias and myalgias. None had long term toxicities. Median progression‐free survival was 43 months. Eighteen patients (36%) died (14 deaths were MCL‐related). The median overall survival has not been reached. Treatment with IR can provide durable remissions in a subset of patients with RR‐MCL, especially those with low Ki67%. The possible benefit of adding other therapies in combination with IR in RR‐MCL is under exploration.     

Characterization of ibrutinib‐sensitive and ‐resistant mantle lymphoma cells

Ibrutinib inhibits Bruton tyrosine kinase (BTK), a key component of early B‐cell receptor (BCR) signalling pathways. A multicentre phase 2 trial of ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL) demonstrated a remarkable response rate. However, approximately one‐third of patients have primary resistance to the drug while other patients appear to lose response and develop secondary resistance. Understanding the molecular mechanisms underlying ibrutinib sensitivity is of paramount importance. In this study, we investigated cell lines and primary MCL cells that display differential sensitivity to ibrutinib. We found that the primary cells display a higher BTK activity than normal B cells and MCL cells show differential sensitivity to BTK inhibition. Genetic knockdown of BTK inhibits the growth, survival and proliferation of ibrutinib‐sensitive but not resistant MCL cell lines, suggesting that ibrutinib acts through BTK to produce its anti‐tumour activities. Interestingly, inhibition of ERK1/2 and AKT, but not BTK phosphorylation per se, correlates well with cellular response to BTK inhibition in cell lines as well as in primary tumours. Our study suggests that, to prevent primary resistance or to overcome secondary resistance to BTK inhibition, a combinatory strategy that targets multiple components or multiple pathways may represent the most effective approach.     

布鲁顿酪氨酸激酶抑制剂联合硼替佐米对人多发性骨髓瘤细胞的作用及其机制

目的 探讨布鲁顿酪氨酸激酶(Bruton,s tyrosine kinase,BTK)抑制剂依鲁替尼(ibrutinib)和AVL-292单药及联合蛋白酶体抑制剂硼替佐米对人多发性骨髓瘤细胞系H929和RPMI8226的作用及其机制.方法 用不同浓度的依鲁替尼、AVL-292单药以及联合硼替佐米处理H929、RPMI8226细胞.采用CCK-8法检测细胞增殖情况,流式细胞术检测细胞凋亡情况,蛋白质印迹法检测药物处理前后细胞内BTK信号通路蛋白及凋亡相关蛋白的表达水平.结果 依鲁替尼和AVL-292均可抑制H929、RPMI8226细胞增殖,其抑制作用呈浓度依赖性,依鲁替尼对H929、RPMI8226细胞48 h的半数抑制浓度(median inhibitory concentration,IC50)分别为(10.41±3.29) μmol/L和(51.65±13.58) μmol/L,AVL-292对H929、RPMI8226细胞48 h的IC50分别为(7.77±2.99) μmol/L和(6.44±1.06) μmol/L.不同浓度的依鲁替尼(5、10 μmol/L)和AVL-292(5、10 μmol/L)分别与不同浓度的硼替佐米(5、10、20、50 nmol/L)联合应用对H929、RPMI8226细胞增殖的抑制率均高于相应浓度单药组(P＜0.05,P＜0.01),不同组合的协同系数R均＞1.0.10 μmol/L依鲁替尼、10 μmol/L AVL-292和20 nmol/L硼替佐米单独作用48 h后,H929细胞的凋亡率分别为(15.12±1.59)％、(18.23±6.38)％和(10.71±1.62)％,均高于对照组[(6.46±1.18)％;P＜0.05,P＜0.01];RPMI8226细胞的凋亡率分别为(9.29±1.44)％、(15.01±4.99)％和(7.58±1.13)％,10 μmol/L依鲁替尼和10 μmol/L AVL-292单药组与对照组[(5.54±1.61)％]比较差异均有统计学意义(P＜0.05);10μmol/L依鲁替尼和10 μmol/L AVL-292分别与20 nmol/L硼替佐米联合后,H929细胞凋亡率分别为(40.31±3.94)％和(51.55±6.39)％,RPMI8226细胞凋亡率分别为(31.86±1.93)％和(43.23±4.03)％,均高于相应单药组(P＜0.01).10 μmol/L依鲁替尼单药和10 μmol/L AVL-292单药作用24 h后,H929细胞内BTK、NF-κB p65、Akt和ERK的磷酸化水平及Bcl-XL蛋白表达水平均较对照组降低(P＜0.05),cleaved caspase-3表达水平均较对照组升高(P＜0.01);两药分别联合20 nmol/L硼替佐米后,对上述蛋白的调节作用均较相应单药组增强(P＜0.05,P＜0.01).结论 BTK抑制剂依鲁替尼和AVL-292对多发性骨髓瘤细胞系H929、RPMI8226有增殖抑制和凋亡诱导作用,并与蛋白酶体抑制剂硼替佐米有协同作用,其机制可能与抑制细胞内BTK活性及下游NF-κB、Akt、ERK信号通路活性,下调抗凋亡蛋白Bcl-xL表达、激活caspase-3依赖的凋亡途径有关.     

依鲁替尼对伯基特淋巴瘤细胞生长抑制及诱导凋亡的作用及机制研究*

目的：研究依鲁替尼（ibrutinib）在体外对伯基特淋巴瘤细胞株Namawal的作用,探讨其可能的分子机制。方法：应用CCK8法,细胞周期分析法检测依鲁替尼作用于Namawal细胞株后,对其增殖、细胞周期等细胞生物学的影响;应用免疫荧光电镜观察药物作用该细胞株后48H细胞核变化;应用免疫印迹法检测ibrutinib作用于Namawal后BTK信号通路相关蛋白的变化。结果：经依鲁替尼处理后的Namawal细胞增殖受到明显抑制;依鲁替尼下调BTK信号通路上相关蛋白活性。结论：依鲁替尼通过抑制p-BTK活性抑制细胞增殖,诱导肿瘤细胞凋亡,是治疗Burkitt淋巴瘤的潜在新药。     

Progress in the management of chronic GVHD insights into novel therapies to treat and manage GVHD lasting longer than 12 Months

Chronic graft-versus-host disease (cGVHD) is a major cause of poor outcomes after hematopoietic stem cell transplantation (HCT). An increased understanding of the pathobiology of cGVHD has led to the development of novel therapies. This review summarized the underlying pathogenesis of cGVHD and has provided considerations for integrating new agents into practice.     

Treatment of patients with Waldenström macroglobulinaemia: clinical practice guidelines from the Myeloma Foundation of Australia Medical and Scientific Advisory Group

Waldenström macroglobulinaemia (WM) is an indolent B‐cell malignancy characterised by the presence of immunoglobulin M (IgM) paraprotein and bone marrow infiltration by clonal small B lymphocytes, plasmacytoid lymphocytes and plasma cells. The symptoms of WM are protean, often follow an asymptomatic phase and may include complications related to the paraneoplastic effects of IgM paraprotein. The revised 2016 World Health Organization classification includes the MYD88 L265P mutation, which is seen in >90% of cases, within the diagnostic criteria for WM. While treatment of WM has often been considered together with other indolent B cell lymphomas, there are unique aspects of WM management that require specific care. These include the unreliability of IgM and paraprotein measurements in monitoring patients prior to and after treatment, the lack of correlation between disease burden and symptoms and rituximab‐induced IgM flare. Moreover, while bendamustine and rituximab has recently been approved for reimbursed frontline use in WM in Australia, other regimens, including ibrutinib‐ and bortezomib‐based treatments, are not funded, requiring tailoring of treatment to the regional regulatory environment. The Medical and Scientific Advisory Group of the Myeloma Foundation Australia has therefore developed clinical practice guidelines with specific recommendations for the work‐up and therapy of WM to assist Australian clinicians in the management of this disease.     

A Perfect Storm: Tyrosine Kinase Inhibitor-Associated Polymorphic Ventricular Tachycardia

Background

Oral tyrosine kinase inhibitors (TKIs) are becoming increasingly common in oncology practice due to ease of administration and patient preference. This class of medications is relatively unknown to emergency physicians.

Indirect Treatment Comparisons of Ibrutinib Versus Physician’s Choice and Idelalisib Plus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia

Purpose

Treatment options for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL) are limited. Until recently, few effective treatment options existed, and even with the advent of new agents, studies evaluating comparative efficacy are scarce. In the Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE) Phase III study, ibrutinib, an oral, once-a-day, first-in-class covalent Bruton tyrosine kinase inhibitor, improved progression-free survival (PFS) and overall survival (OS) compared with ofatumumab (PFS hazard ratio [HR] = 0.106 and OS HR = 0.369 [adjusted for crossover] at a median of 16 months’ follow-up). We sought to establish the relative efficacy of ibrutinib versus other treatment options for patients with R/R CLL using indirect comparison methods.