硼替佐米治疗浆细胞病患者临床不良反应分析

目的：了解硼替佐米不良反应的特点,为临床使用提供参考。方法：通过对2007年至2009年之间临床确诊的浆细胞病患者使用硼替佐米的观察,收集不良反应报告表进行统计分析。结果：硼替佐米在治疗浆细胞病患者过程中不良反应发生率为乏力12.9%、腹泻35.5%、血小板减少16.1%、带状疱疹19.4%、外周神经病16.1%。结论：硼替佐米在临床应用中易出现不良反应,但严重的死亡病例未见。应进一步加强对硼替佐米临床应用过程中不良反应的监测,积极开展其不良反应发生机理的研究,促进该药品安全性的再评价。     

皮下注射硼替佐米治疗多发性骨髓瘤研究进展

多发性骨髓瘤是以骨髓中克隆性浆细胞恶性增殖为特征的肿瘤。有硼替佐米参与的联合化疗大大改善了患者的预后。周围神经病变是其常见不良反应之一,严重的不良反应通常会导致需要减低用药剂量或停止治疗,影响了其在临床中的应用。将硼替佐米由传统静脉快速注射改为皮下注射并不影响临床疗效,且具有更好的安全性。皮下硼替佐米给药为MM患者提供了一种新的治疗选择方式,本文将对皮下注射硼替佐米治疗多发性骨髓瘤的研究进展作一综述。     

硼替佐米治疗难治性浆细胞疾病导致的肺损伤

目的　观察硼替佐米治疗难治性浆细胞疾病引发肺损伤情况。方法　回顾分析３例难治性浆细胞疾病患者应用硼替佐米后出现肺损伤临床资料。结果　３例难治性浆细胞疾病患者均在应用硼替佐米４～１２小时后出现严重低氧血症,呼吸功能衰竭,细菌培养阴性,经验性抗细菌治疗无效,大剂量激素治疗可挽救部分患者。结论　疾病晚期、高肿瘤负荷可能是难治性浆细胞疾病患者应用硼替佐米后引发肺损伤的部分原因。     

硼替佐米治疗多发性骨髓瘤导致肺损害、心功能衰竭1例并文献复习

 硼替佐米作为一种蛋白酶体抑制剂,已愈来愈广泛应用于各种浆细胞疾病治疗,其常见不良反应包括周围神经毒性、血小板减少和消化道反应,多易于控制和预防,而有关硼替佐米导致严重心、肺损伤的报告较少。虽然硼替佐米治疗浆细胞疾病出现肺损伤发生率低,但一旦发生、进展迅速、预后差、死亡率极高。本文报道1例初治多发性骨髓瘤患者硼替佐米治疗后同时引发严重肺损伤、心功能衰竭,并文献复习,以引起临床注意。     

硼替佐米联合化疗治疗原发性浆细胞白血病一例并文献复习

目的探讨硼替佐米联合化疗治疗原发性浆细胞白血病（PCL）的疗效。方法报告一例原发性PCL患者使用硼替佐米联合化疗的临床资料,并文献复习。原发性PCL患者常规化疗无效,PCL病情进展,使用硼替佐米联合化疗（硼替佐米＋地塞米松＋沙利度胺）治疗。结果经过硼替佐米联合化疔治疗2个疗程后,患者获得完全缓解（CR）。其后患者又接受2个疗程硼替佐米联合化疗,保持在CR状态。结论硼替佐米联合化疗治疗PCL有效。     

国产与进口硼替佐米治疗多发性骨髓瘤的真实世界疗效、安全性及经济学对比

目的:在真实世界中,对比以国产与进口原研硼替佐米为基础的方案治疗多发性骨髓瘤的疗效、不良反应及治疗费用。方法:101例多发性骨髓瘤患者,应用进口原研硼替佐米治疗组48例,国产硼替佐米治疗组53例,比较两组患者的治疗反应率、不良反应发生率及治疗费用。结果:随访截止至2018年12月31日,两组患者4个疗程结束后的完全缓解（complete response,CR）率、总缓解率（overall response rate,ORR）差异无统计学意义（P＞0.05）;根据不同危险因素进行分层,两组患者的CR率、ORR差异也无统计学意义（P＞0.05）;在血液学与非血液学不良反应方面差异无统计学意义（P＞0.05）;国产硼替佐米各个疗程后总花费均低于进口硼替佐米,差异具有统计学意义（P＜0.05）。结论:在真实世界中,国产硼替佐米与进口原研硼替佐米治疗多发性骨髓瘤患者在早期诱导缓解方面的临床疗效相当,安全性相当,但国产硼替佐米价格相对低廉,可以广泛应用。     

PCAD方案治疗原发性浆细胞白血病2例并文献复习

目的:探讨原发性浆细胞白血病的有效治疗方案。方法:应用PCAD（硼替佐米、环磷酰胺、脂质体阿霉素、地塞米松）方案治疗2例老年原发性浆细胞白血病的患者。同时对原发性浆细胞白血病的诊治进行文献复习。结果:2例患者总生存期（OS）大于24个月。结论:原发性浆细胞白血病病情进展迅速,预后差,以硼替佐米为基础的PCAD方案治疗老年原发性浆细胞白血病安全有效。     

硼替佐米联合化疗治疗浆细胞白血病的疗效观察

目的评估硼替佐米联合化疗治疗浆细胞白血病(plasma cell leukemia,PCL)的疗效和不良反应。方法 11例浆细胞白血病经骨髓穿刺确诊,给予含硼替佐米方案化疗。硼替佐米给药方案为1.3 mg/m~2,d1,d4,d8,d11;联合的化疗方案包括地塞米松(BD),吡柔比星加地塞米松(PAD),马法兰加泼尼松(VMP)等。按照国际骨髓瘤工作组制定的疗效标准评估疗效,按照NCI标准评估不良反应。结果 11例患者共完成37个治疗周期,平均每例3.4个周期。11例患者中,2例获得CR,6例获得VGPR,1例获得PR,总反应率达81.8%。中位生存期17.2个月,与历史数据相比有明显区别(17.2个月vs 5.6个月).不良反应主要是骨髓抑制和感染。结论硼替佐米联合化疗治疗浆细胞白血病的疗效确切,不良反应可耐受。     

硼替佐米治疗恶性浆细胞病的临床观察

目的：观察硼替佐米（bortezomib）治疗恶性浆细胞病的临床疗效和不良反应。方法：2007年2-10月复旦大学附属华山医院血液科收治的10例恶性浆细胞病患者,接受VD方案（硼替佐米1.1～1.3mg/m^2,第1、4、8、11天;地塞米松3mg/d,第1～4天,第8～11天）、VDT方案（VD方案加沙利度胺100～150mg/d,第1～28天）或PVADT方案（硼替佐米1.1～1.3mg/m^2,第1、4、8、11天;地塞米松30mg/d,第1～4天,第8～11天;长春地辛1mg/d,第1～4天,脂质体多柔比星20mg第1、3天;沙利度胺100mg/d,第1～28天）化疗,4周为1疗程。结果：10例患者均在第1疗程后显示治疗反应,1例获得非常好的部分缓解（very good partial remission,VGPR）、9例获得部分缓解（partial remission,PR）,总有效率为100%;坚持治疗的9例患者,现2例处于完全缓解（complete remission,CR）、1例VGPR、6例PR,总有效率为100%。不良反应主要包括末梢神经炎、血小板减少、胃肠道反应、乏力以及潜在的免疫抑制作用。结论：硼替佐米对于恶性浆细胞病有显著疗效;存在一些不良反应,但患者耐受良好。     

硼替佐米治疗难治性套细胞淋巴瘤一例并文献复习

 目的　探讨硼替佐米在难治性套细胞淋巴瘤（MCL）治疗中的价值。方法　分析1例应用硼替佐米治疗的MCL患者的临床资料,并复习相关文献。结果　患者应用R-CHOP方案化疗后5月余疾病进展,改用硼替佐米化疗后达完全缓解,随访14个月,疾病仍处于缓解状态。结论　硼替佐米在治疗复发／难治的MCL中有积极作用,并且患者不良反应在可控范围。     

Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma: a phase 2 trial of the Minnie Pearl Cancer Research Network

BACKGROUND: The purpose of the current study was to evaluate the efficacy and toxicity of weekly bortezomib in the treatment of patients with recurrent/refractory multiple myeloma. METHODS: A total of 40 patients with multiple myeloma who had received either 1 or 2 previous treatment regimens were treated with bortezomib at a dose of 1.6 mg/m(2) intravenously for 4 consecutive weeks, followed by 1 week without treatment. Responses were measured using International Myeloma Working Group criteria. RESULTS: Twenty-two patients (55%; 95% confidence interval, 40%-70%) achieved objective responses to treatment, with a median response duration of 16 months. The median progression-free survival for all patients was 9.6 months, with a 1-year progression-free survival rate of 39%. The 1-year and 2-year overall survival rates were 75% and 51%, respectively. Weekly bortezomib was generally well tolerated; grade 3/4 (using the National Cancer Institute Common Toxicity Criteria [version 3.0]) neutropenia (13%), thrombocytopenia (20%), fatigue (15%), diarrhea (13%), and neuropathy (10%) were experienced by a minority of patients. CONCLUSIONS: In the current study, a schedule of weekly bortezomib was found to be effective and well tolerated in patients with previously treated multiple myeloma. Although the response rate and duration appear comparable to those achieved with twice-weekly bortezomib, the relative efficacy of these 2 schedules cannot be determined definitively on the basis of this phase 2 study. A weekly schedule of bortezomib is a reasonable option for patients who have logistic difficulties receiving a twice-weekly schedule, and is an attractive schedule for incorporation into combination regimens.     

Efficacy and safety of bortezomib in patients with plasma cell leukemia

BACKGROUND: The prognosis of patients with plasma cell leukemia (PCL), an aggressive variant of multiple myeloma (MM), is usually poor. Bortezomib is the first proteasome inhibitor approved for the treatment of advanced MM. Currently available information regarding the role of bortezomib in PCL is scanty and derives from anecdotal, single-case reports. METHODS: The authors conducted a retrospective survey of unselected Italian patients with primary or secondary PCL who were treated with bortezomib outside of clinical trials. Twelve evaluable patients were recorded who had received bortezomib for 1 to 6 cycles as either a single agent or variously combined with other drugs. Three patients were treated with bortezomib as frontline therapy, and 9 patients received bortezomib after 1 to 4 lines of chemotherapy, including autologous stem cell transplantation and thalidomide. RESULTS: According to the International uniform response criteria of the International Myeloma Working Group, 5 partial responses (defined as a reduction in M-protein of >50%), 4 very good partial responses (defined as a reduction of >90% in M-protein), and 2 complete responses (defined as negative immunofixation) were achieved, for a response rate of 92%. Responses did not appear to be influenced by previous treatments or by other clinical or biologic parameters, including chromosome 13 deletion or the combination of bortezomib with other drugs. The median progression-free and overall survivals after bortezomib were 8 months and 12 months, respectively. At the time of last follow-up, 8 patients were alive 6 to 21 months after treatment with bortezomib, 4 of whom were in very good partial or complete responses. Grade 3/4 hematologic or neurologic toxicities (graded according to the Common Terminology Criteria for Adverse Events [CTCAE; version 3]) were reported to occur in 9 patients and 1 patient, respectively, whereas 6 patients experienced possible or documented infections. CONCLUSIONS: Bortezomib appears to be an effective drug for PCL that could significantly improve the usually adverse clinical outcome of these patients.     

Synergistic effect of panobinostat and bortezomib on chemoresistant acute myelogenous leukemia cells via AKT and NF-κB pathways

In this study, we investigated the synergistic effects of panobinostat and bortezomib on adriamycin-resistant HL60/ADR cells and refractory acute myelogenous leukemia (AML) primary cells. Combination of both agents had synergistic cytotoxicity on these cells, and increased the sensitivity of HL60/ADR cells to adriamycin. Panobinostat plus bortezomib was shown to modulate multiple apoptotic and drug metabolic related molecules, including activation of caspases, down-regulation of XIAP, Bcl-2 and MRP1. These effects were likely to be mediated via inhibition of AKT and NF-κB pathways. These findings provide evidence for clinic protocols using panobinostat and borezomib to overcome drug resistance in refractory AML patients.     

Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitors.

PURPOSE: The purpose of this study was to examine interactions between the proteasome inhibitor bortezomib (Velcade) and the histone deacetylase (HDAC) inhibitors sodium butyrate and suberoylanilide hydroxamic acid in human multiple myeloma (MM) cells that are sensitive and resistant to conventional agents. EXPERIMENTAL DESIGN: MM cells were exposed to bortezomib for 6 h before the addition of HDAC inhibitors (total, 26 h), after which reactive oxygen species (ROS), mitochondrial dysfunction, signaling and cell cycle pathways, and apoptosis were monitored. The functional role of ROS generation was assessed using the free radical scavenger N-acetyl-l-cysteine. RESULTS: Preincubation with a subtoxic concentration of bortezomib markedly sensitized U266 and MM.1S cells to sodium butyrate- and suberoylanilide hydroxamic acid-induced mitochondrial dysfunction; caspase 9, 8, and 3 activation; and poly(ADP-ribose) polymerase degradation; resulting in synergistic apoptosis induction. These events were associated with nuclear factor kappaB inactivation, c-Jun NH(2)-terminal kinase activation, p53 induction, and caspase-dependent cleavage of p21(CIP1), p27(KIP1), and Bcl-2, as well as Mcl-1, X-linked inhibitor of apoptosis, and cyclin D1 down-regulation. The bortezomib/HDAC inhibitor regimen markedly induced ROS generation; moreover, apoptosis and c-Jun NH(2)-terminal kinase activation were attenuated by N-acetyl-l-cysteine. Dexamethasone- or doxorubicin-resistant MM cells failed to exhibit cross-resistance to the bortezomib/HDAC inhibitor regimen, nor did exogenous interleukin 6 or insulin-like growth factor I block apoptosis induced by this drug combination. Finally, bortezomib/HDAC inhibitors induced pronounced lethality in primary CD138(+) bone marrow cells from MM patients, but not in the CD138(-) cell population. CONCLUSIONS: Sequential exposure to bortezomib in conjunction with clinically relevant HDAC inhibitors potently induces mitochondrial dysfunction and apoptosis in human MM cells through a ROS-dependent mechanism, suggesting that a strategy combining these agents warrants further investigation in MM.     

siNrf2对万珂诱导甲状腺癌细胞凋亡影响及其机制的探讨

目的:明确Nrf2对蛋白酶体抑制剂万珂诱导甲状腺癌细胞凋亡的影响及其作用途径.方法:选取Nrf2高表达的8305C细胞,用微小RNA干扰技术转染细胞,采用实时定量PCR法和蛋白质印迹法分析封闭效果,而细胞内GCLCmRNA的表达、还原型谷胱甘肽(GSH)的含量和细胞凋亡率,分别由实时定量PCR法、比色法和流式细胞仪法测得.并测定siNrf2对万珂诱导其他甲状腺癌细胞凋亡的影响.结果:与对照组相比,siNrf2组在培养液和万珂处理中Nrf2mRNA和蛋白都显著减少,P＜0.01;随机序列核酸siRNA和错位型siNrf2差异无统计学意义,P＞0.05.与对照组相比,siNrf2能够增加万珂诱导8305C、8505C、KTC1和KTC3的细胞凋亡率,差异均有统计学意义,P＜0.01;FRO和KTC2的细胞凋亡率差异无统计学意义,P＞0.05.与随机序列核酸siRNA组相比,空白对照组中siNrf2转染组GCLCmRNA及GSH减少,P＜0.05;万珂处理组中siNrf2转染组两者减少更显著,P＜0.01.GSH和NAC(GSH的前体并能提高GSH的含量)抑制了siNrf2促万珂诱导甲状腺癌细胞凋亡作用.结论:Nrf2抵消万珂诱导甲状腺癌细胞凋亡作用,至少部分是通过GCLC转录激活和随后GSH的生成实现的.     

Neurotoxicity of bortezomib therapy in multiple myeloma: a single-center experience and review of the literature

BACKGROUND: Bortezomib is active in heavily pretreated multiple myeloma patients; the dose-limiting toxicity is peripheral neuropathy (PN). METHODS: The authors retrospectively reviewed the incidence, severity, and risk factors for PN in 78 patients who received bortezomib. The median age was 57 years (range, 33-80 years), 62% of patients were men, and 37% of patients were African Americans. Seventeen patients (22%) had diabetes mellitus (DM), and 66 patients (85%) had received thalidomide. Before bortezomib treatment, 37% of the patients reported subjective, grade 1 or 2 PN. Patients received bortezomib alone (n = 10 patients) plus dexamethasone (n = 36 patients) and thalidomide (n = 20 patients) or chemotherapy (n = 12 patients). PN affected 52% of patients, including grade 3 and 4 PN in 15% and 7%, respectively. RESULTS: Twelve patients stopped bortezomib because of side effects that included PN (n = 9 patients), diarrhea (n = 2 patients) and cytomegalovirus pneumonia (n = 1 patient); 11 patients had dose reductions because of PN. Grade 4 PN affected 6 patients (sensory, n = 4 patients; motor/sensory, n = 2 patients). The onset of grade 4 PN was sudden rather than cumulative. Factors that were predictive of PN grade were baseline PN (P = .002), prior thalidomide use (P = .03), and the presence of DM (P = .03). Multiple myeloma responses included complete, near complete, and partial responses in 5% of patients, 10% of patients, and 27% of patients, respectively. Responses were independent of PN and of whether bortezomib was combined with chemotherapy or thalidomide. Patients remained on therapy longer for a median of 5 cycles (range, 2-36 cycles) when they received bortezomib plus thalidomide versus 3 cycles (range, 1-19 cycles) for the other combinations. PN therapy was mostly supportive. It was noteworthy that 6 of 9 patients with PN who received lenalidomide as salvage therapy after bortezomib had significant improvement in their symptoms. CONCLUSIONS: The risk of bortezomib-related PN was greater in patients who had PN and DM at baseline. The authors concluded that an unexpected, symptomatic improvement of PN on lenalidomide is worth further investigation.     

硼替佐米联合地塞米松治疗24例多发性骨髓瘤的疗效分析

背景及目的:硼替佐米(bortezomib)是一种有效、可逆性的蛋白酶体抑制剂,通过诱导骨髓瘤细胞的凋亡,在骨髓瘤患者的治疗中发挥持久的疗效。本研究旨在观察硼替佐米联合地塞米松治疗初治、难治/复发多发性骨髓瘤(multiple myeloma,MM)患者的疗效和毒副作用,及该方案在肾功能不全患者中应用的安全性。方法:24例MM患者接受硼替佐米联合地塞米松方案治疗,每3周为一个疗程。所有患者共接受中位3个疗程(1～8个疗程)的化疗。采用EBMT疗效评价标准评价疗效,按国立癌症研究所的常规毒性判定标准评价不良反应。结果:全组中位随访4个月,总有效率79.2%(19/24)。轻链型患者CR率57.1%(4/7),明显高于非轻链型患者5.9%(1/17),差异有统计学意义(P=0.014)。7例合并肾功能不全的患者与肾功能正常患者的疗效相近,差异无统计学意义(P=0.272)。Ⅲ～Ⅳ级不良反应包括白细胞减少(2/24,8.3%)、血小板减少(8/24,33.3%)、腹泻(2/24,8.3%)和乏力(1/24,4.2%),经对症治疗或推迟化疗后均可恢复。结论:硼替佐米联合地塞米松方案治疗MM患者有明显疗效,在轻链型患者疗效更加显著。副作用可以耐受,在合并肾功能不全的患者可安全应用。     

Weekly doxorubicin versus doxorubicin every 3 weeks in cyclophosphamide, doxorubicin, and cisplatin chemotherapy for non-small cell lung cancer

A prospective randomized study was done to determine the effect of different doxorubicin (Adriamycin [ADR], Adria Laboratories, Columbus, OH) administration (schedules every week versus every 3 weeks) on the productivity of a cyclophosphamide, ADR, cisplatin (CAP) chemotherapy regimen for patients with non-small cell lung cancer (NSCLC). Electrocardiograms, multigated cardiac scans, echocardiograms, and endomyocardial biopsies were done serially for cardiac monitoring. Of 102 patients, 47 ahd inoperable limited disease (LD), 47 had extensive disease (ED), and eight had no evidence of disease. In the last group chemotherapy was given adjuvantly. Fifty-one patients were entered into each treatment arm. The groups were formed according to extent of disease and were comparable in terms of patient characteristics. In these groups, the overall response rates using both schedules in LD patients were similar: in patients without chest irradiation previously, there was a response of 35% with ADR weekly, and 31% with ADR triweekly; in LD patients with chest irradiation previously, the response was 20% with ADR weekly, and 25% with ADR triweekly; and in ED patients, 16% with ADR weekly, and 11% with ADR triweekly. There was no significant difference in survival between the two treatment groups. However, results for all responders suggested a longer duration of response with weekly than with triweekly ADR (complete plus partial response: 35.8 versus 11.4 weeks, P = 0.06; minor response: 34 versus 11.5 weeks, P = 0.003, respectively). Results also suggested that weekly ADR was less cardiotoxic than triweekly ADR: 29% of patients in the former group had no changes or only minor changes in endomyocardial biopsy results, whereas all patients in the latter group had at least grade 0.5 changes at a similar dosage. The median doses of weekly ADR were higher at the same endomyocardial biopsy-defined toxicity levels. No correlation was found between toxic effects defined by endomyocardial biopsy results and those defined by noninvasive monitoring techniques, although the number of patients assessed was small. Weekly ADR produced less granulocytopenia and a lower incidence of fever (6% versus 16%, P less than 0.001) than did triweekly ADR. Alopecia, nausea, vomiting, and diarrhea were significantly less for weekly ADR than triweekly Adr (P less than 0.0005, less than 0.0005, and less than 0.005, respectively). These data suggest that weekly ADR can achieve the same therapeutic results as the standard triweekly regimen with less cardiotoxicity, myelotoxicity, alopecia, diarrhea, nausea, and vomiting in patients with NSCLC.     

Bortezomib in combination with conventional chemotherapeutic agents for multiple myeloma compared with bortezomib alone

BACKGROUND: Recent studies have demonstrated synergy between bortezomib and a number of conventional cytotoxic agents. This study examined whether or not the speed of the response, progression and safety from a combination treatment of bortezomib with common chemotherapeutic drugs is superior to bortezomib monotherapy. METHODS: Fifty-seven patients with relapsed, refractory multiple myeloma (MM) who had received at least two cycles of treatment including bortezomib were enrolled in this study. The median age was 56 (35-79) years and 49.1% were male. Thirty-two patients were treated with bortezomib alone and 25 were treated with chemotherapeutic agents that were given in combination with bortezomib. The monoclonal immunoglobulin (mIg) or free light chain (FLC) concentrations were determined in the sera before and after two cycles of bortezomib treatment. The adverse events were assessed and graded according to the NCI Common Toxicity Criteria (version 2.0). RESULTS: Thirty-one of the 57 patients (54.4%) attained an early objective response (EOR) after the second bortezomib treatment, defined as a >/=50% decrease in the serum mIg or FLC concentration. Improvements in the response were observed when common chemotherapeutic agents were added to bortezomib monotherapy. In patients who received bortezomib combined with chemotherapeutic agents, 19 out of 25 patients (76%) showed an EOR, whereas 12 out of 32 patients (37.5%) given bortezomib monotherapy achieved an EOR after the second cycle of bortezomib treatment (P = 0.004); the median decrease from the baseline in the paraprotein level was 74.6 +/- 5.9 and 39.7 +/- 4.2%, respectively (P = 0.003). A statistically significant elevation of serum lactic dehydrogenase (P = 0.007) and alkaline phosphatase (P = 0.027) from baseline within two cycles of bortezomib treatment was observed in responding patients. With the combination treatment, peripheral neuropathy of >/=Grade II occurred in 12 out of 25 patients (48%) compared with 12 of 32 (37.5%) in those given bortezomib alone (P = 0.589). The median time to progression of disease was similar in the two groups (359 +/- 43.5 versus 365 +/- 103.5, P = 0.688). The multivariate Cox regression model showed that a high serum albumin and low beta2-microglobulin are favorable factors for the progression-free survival following bortezomib treatment. CONCLUSIONS: Bortezomib in combination with common chemotherapeutic agents is more active in the treatment of relapsed, refractory MM than with bortezomib alone. However, more effective post-bortezomib treatment is needed to reduce the rate of disease progression particularly in patients with high tumor burden.