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。     

硼替佐米治疗多发性骨髓瘤后严重肺损伤二例报告并文献复习

目的 分析复发多发性骨髓瘤(MM)患者接受硼替佐米治疗后患者出现严重肺损伤的情况,提高对硼替佐米副作用的认识.方法 报道2例复发MM患者接受硼替佐米联合地塞米松或沙利度胺的化疗过程中出现严重肺损伤并复习文献.结果 2例复发MM患者在应用硼替佐米治疗过程中出现哮喘、呼吸困难、发热、低氧血症.胸部X线片提示肺部感染,细菌学检查无阳性发现,广谱抗生素治疗无效,糖皮质激素治疗有效.结论 硼替佐米治疗MM导致严重肺损伤尽管少见,但预后凶险,值得重视.预防性应用激素可能降低肺损伤的发生率.     

沙利度胺联合干扰素和硼替佐米治疗复发、难治性套细胞淋巴瘤一例并文献复习

目的：初步观察沙利度胺联合干扰素（IFN）和硼替佐米治疗复发、难治性套细胞淋巴瘤（MCL）的临床疗效。方法报道1例先后应用沙利度胺联合IFN和硼替佐米治疗的复发、难治性MCL患者临床资料,并进行文献复习。结果该患者对化疗原发耐药,应用沙利度胺联合IFN治疗后达完全缓解,疾病无进展生存期41.7个月;复发后给予二线方案化疗无效,应用硼替佐米治疗后达部分缓解,目前总生存为56.7个月。结论沙利度胺联合IFN和硼替佐米治疗复发、难治性MCL有效。     

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。     

硼替佐米治疗难治性华氏巨球蛋白血症一例并文献复习

 目的　报道应用硼替佐米治疗1例难治性华氏巨球蛋白血症（WM）患者的疗效, 结合文献复习进一步了解硼替佐米治疗难治WM的现状。方法　确诊为WM的患者在接受氟达拉滨及地塞米松（FD方案）治疗2个疗程后患者达到次要缓解,继续给予2个疗程治疗后,病变进展。换用环磷酰胺、长春新碱及泼尼松（COP）方案无效,改用硼替佐米治疗。结果　3个疗程硼替佐米治疗后,患者达到部分缓解。在治疗过程中,患者主要不良反应为皮疹以及单纯疱疹。结论　硼替佐米是治疗难治以及复发WM的有效药物,患者耐受性好。     

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。     

硼替佐米联合VMCLP方案治疗复发难治性急性淋巴细胞白血病一例并文献复习

 【摘要】　目的　探讨硼替佐米联合VMCLP方案（简称VMCLP-硼替佐米方案）治疗复发难治性急性淋巴细胞白血病（ALL）的疗效。方法　采用VMCLP-硼替佐米方案（米托蒽醌 10 mg 第1天至第3天,长春地辛 4 mg 第1、8天,泼尼松片 80 mg 第1天至第8天,环磷酰胺 0.8 g 第2、5天,左旋门冬酰胺酶 1万U 第2天至第7天,硼替佐米 2.25 mg 第7、10、14、17天）治疗1例复发难治性ALL,并结合相关文献对其作用机制进行讨论。结果　应用VMCLP-硼替佐米方案治疗1个疗程后,患者取得完全缓解,患者的体能状况评分令人满意。结论　VMCLP-硼替佐米方案为复发难治性ALL的治疗提供了新的治疗策略。     

硼替佐米治疗多发性骨髓瘤的疗效

目的:观察硼替佐米治疗多发性骨髓瘤的疗效及不良反应。方法:多发性骨髓瘤患者26例,均给予以硼替佐米为基础的联合方案治疗,患者分别接受2-6个周期治疗。结果:26例患者在接受2个疗程硼替佐米治疗后,其中2例患者完全缓解,7例患者达非常好的部分缓解,16例患者部分缓解,1例患者出现疾病进展。不良反应主要有周围神经病变、血液学毒性、消化道症状以及感染等,经对症支持大部分可以缓解。结论:硼替佐米对于多发性骨髓瘤起效快,有一定程度不良反应,但大部分可逆转。     

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。     

硼替佐米治疗复发难治性套细胞淋巴瘤的研究进展

 复发难治性套细胞淋巴瘤（MCL）的治疗是临床医师面临的严峻挑战。近年来,蛋白酶体抑制剂硼替佐米的应用给复发难治性MCL患者的治疗提供了新方法。就硼替佐米治疗复发难治性MCL的机制、临床疗效以及MCL细胞对硼替佐米耐药产生的机制和应对策略进行综述。     

硼替佐米致周围神经病变27例临床分析

目的:分析和研究硼替佐米致周围神经病变（BIPN）的临床特征。方法:以2014年5月至2015年5月于中国医科大学附属盛京医院血液科住院接受硼替佐米治疗的27例多发性骨髓瘤患者为研究对象,统计分析其治疗过程中周围神经病变发生情况。结果:经硼替佐米方案化疗后,40.7%的患者出现了BIPN,其中初治患者4人,复发难治患者7人;3-4级神经毒性占27.3%（3/11）,其中初治患者1人,复发难治患者2人。复发难治组患者11人既往接受过长春新碱、沙利度胺等神经毒性药物化疗,63.6%的患者产生BIPN,其中2人为3-4级神经毒性。既往糖尿病或酗酒患者共7人,BIPN发生率为85.7%。年轻患者（年龄≤60岁）BIPN发生率为27.3%,低于老年患者（50.0%）。停止治疗后再次评价,81.8%患者症状和体征得到改善。结论:高龄、糖尿病、酗酒,接受过长春新碱、沙利度胺等治疗是硼替佐米致周围神经病变发生的主要危险因素。3-4级神经毒性需要减量或停药,BIPN具有剂量依赖性和可逆性,停止治疗后患者症状和体征会有改善。     

Vorinostat Plus Bortezomib for the Treatment of Relapsed/Refractory Multiple Myeloma: A Case Series Illustrating Utility in Clinical Practice

IntroductionIncreasing numbers of patients are presenting with relapsed/refractory multiple myeloma (MM) following treatment with bortezomib. Therefore, there is a need for effective and well-tolerated treatment strategies after failure of bortezomib-based regimens. Vorinostat, a histone deacetylase inhibitor, has demonstrated antiproliferative and proapoptotic activity alone and in combination with bortezomib in preclinical models of MM. Preliminary results from ongoing phase I trials have demonstrated the clinical activity of vorinostat in combination with bortezomib in patients with MM. This case series reports our experience of combined vorinostat and bortezomib in 6 patients with relapsed/refractory MM after previous bortezomib.Materials and MethodsPatients received oral vorinostat 300 mg or 400 mg once daily (days 1-14) and bortezomib 1.3 mg/m² on days 1, 4, 8, and 11 in a 21-day cycle.ResultsAll patients derived clinical benefit from combined vorinostat and bortezomib, with objective response observed in 5 of the 6 patients (≥ minimal response), including 1 very good partial response; stable disease was observed in the remaining patient. Patients remained on therapy until disease progression. Combined vorinostat and bortezomib therapy was well tolerated: grade 2 nausea and diarrhea were the only adverse events reported. No patients discontinued therapy because of toxicity, and no dose adjustments were required for either agent.ConclusionThese results suggest that combined vorinostat and bortezomib therapy is effective in patients with relapsed/refractory MM after failure of previous bortezomib-based regimens and support further evaluation of this combination in randomized trials.     

硼替佐米治疗12例难治性多发性骨髓瘤

 目的　观察硼替佐米治疗难治性多发性骨髓瘤（MM）的疗效和患者不良反应。方法　12例患者中男9例，女3例，中位年龄67岁，难治性MM患者接受硼替佐米治疗，1.0 mg／m2～1.3 mg／m2，静脉注射，第1、4、8、11天，3周为1个疗程；或者1.6 mg／m2静脉注射，第1、8、15、22天，5周1个疗程。多数患者同时应用地塞米松20～40 mg／d，第1天至第4天；2例同时合用多柔比星脂质体（商品名：楷莱）。疗效采用EBMT标准进行评价，不良反应按照美国国立癌症研究所（NCI）CTCAE评价。结果　中位随访时间6.5（1～13）个月，9例可评价疗效，8例（88.9 ％）有效，其中nCR4例，PR3例，MR1例。7例中断治疗后疾病进展。死亡5例，其中3例为治疗有效后中断治疗者。患者最常见的不良反应为血小板减少，但可以自行恢复。其次为恶心、呕吐、乏力、周围神经毒性、带状疱疹等。结论　硼替佐米治疗难治性MM疗效确凿，患者耐受性好，但需要坚持足疗程治疗。     

硼替佐米为主方案治疗复发难治性多发性骨髓瘤

 目的 探讨硼替佐米联合地塞米松等治疗复发难治性多发性骨髓瘤（MM）的疗效及毒副作用。方法 5例复发难治的MM采用硼替佐米1.1 ~ 1.3 mg／m2,联合地塞米松30 mg ~ 40 mg,第1、4、8、11天;沙利度胺100 ~ 200 mg,第1天至第21天,第4天加或不加表柔比星,3周为1个疗程,每位患者治疗1 ~ 4个疗程。根据欧洲血液病和骨髓移植组（EBMT）标准判断疗效、WHO抗癌药毒副作用的分度标准判断不良反应。结果 5例患者均有效,疗效出现在治疗3周后,1个疗程近似完全缓解（CR）2例,轻微有效（MR）2例,另1例3个疗程后达部分缓解（PR）。患者不良反应主要是贫血、白细胞和血小板减少,其减少的程度和治疗前水平相关,其次为腹泻、末梢神经炎和乏力,经对症处理缓解。结论 硼替佐米联合地塞米松等能有效治疗复发难治性MM,耐受性良好。     

Bortezomib: clinical profile in lymphoproliferative malignancies

In addition to its efficacy in the treatment of multiple myeloma, the proteasome inhibitor bortezomib appears to be active against a variety of other haematological malignancies. In a phase II trial, bortezomib, given twice weekly for 2 weeks of a 3 week cycle to patients with relapsed, refractory or untreated indolent non-Hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL), produced durable responses in 2/7 MCL patients and stable disease in five. Six of eight patients with follicular NHL achieved a durable response (1 CR, 5 PR). In another study, bortezomib was administered to patients with relapsed or refractory indolent or aggressive B-cell lymphoma. Durable responses were seen in 7/12 MCL patients, including three CR. This apparent activity in MCL is particularly encouraging, given its poor prognosis. These early trial results demonstrate that further clinical testing of bortezomib and additional exploration of the multiple biologic effects of proteasome inhibition are warranted in lymphoproliferative malignancies.     

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.     

A Case of Disseminated and Fulminant Plasmacytomas That Developed during Bortezomib Treatment

Multiple myeloma is an incurable and slow growing plasma cell neoplasm. The introduction of new drugs has increased the number of treatment options. Bortezomib, the first-in-class proteasome inhibitor, has been shown to have a significant antitumor activity in the treatment of relapse/refractory patients with multiple myeloma. Additionally, plasmacytomas have shown significant response to bortezomib. In this case report, we describe a patient who developed disseminated and fulminant extramedullary plasmacytomas during combination chemotherapy treatment with bortezomib within a short period, after having shown clinical improvement.     

Panobinostat: A Review in Relapsed or Refractory Multiple Myeloma

Oral panobinostat (Farydak®), a potent nonselective histone deacetylase inhibitor, is approved in several countries for use in combination with bortezomib and dexamethasone in patients with multiple myeloma (MM) [USA] or relapsed and/or refractory MM (EU) who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory drug (IMiD). In a pivotal phase III trial (PANORAMA 1) in patients with relapsed or relapsed and refractory MM who had received one to three previous lines of therapy, progression-free survival (PFS) was significantly prolonged with panobinostat plus bortezomib and dexamethasone compared with placebo plus bortezomib and dexamethasone. The significantly favourable effect of panobinostat- versus placebo-based treatment on PFS was also observed in a subgroup analysis of patients who had previously received an IMiD, bortezomib plus an IMiD, or at least two lines of treatment including bortezomib and an IMiD. Panobinostat plus bortezomib and dexamethasone had a generally manageable tolerability profile, with the most frequent grade 3–4 adverse events being myelosuppression, diarrhoea, asthenia or fatigue, peripheral neuropathy and pneumonia. Thus, panobinostat, in combination with bortezomib and dexamethasone, is a useful addition to the available treatment options for patients with relapsed or refractory MM.     

Bortezomib: a valuable new antineoplastic strategy in multiple myeloma

Although the treatment of multiple myeloma has improved over the past decade, the disease remains incurable. Bortezomib, a first-in-class selective proteasome inhibitor, was approved in the United States in 2003 and the European Union in 2004 for the treatment of relapsed and refractory multiple myeloma in patients who have received at least 2 prior therapies and demonstrated disease progression on the last therapy. In vitro, bortezomib induces apoptosis of multiple myeloma cells and inhibits cell adhesion within the bone marrow microenvironment. Preclinical and clinical data have shown that bortezomib enhances sensitivity and reverses resistance to standard therapeutic agents used in multiple myeloma. The efficacy and safety of bortezomib was established in patients with relapsed and/or refractory disease. In a large phase III trial in patients with relapsed multiple myeloma, median time to progression and overall survival were significantly improved with bortezomib compared with high-dose dexamethasone. Importantly, the preliminary results of several phase I and II studies are also showing high antimyeloma activity of bortezomib alone or in combination with dexamethasone or cytotoxic agents such as doxorubicin, melphalan, or thalidomide in patients with newly diagnosed multiple myeloma. Ideally, the introduction of bortezomib will result in a significant improvement in the future management of multiple myeloma.