沙利度胺联合MP方案治疗老年多发性骨髓瘤临床观察

目的 观察沙利度胺联合MP方案(马法兰、强的松)与单用MP方案比较治疗老年多发性骨髓瘤(MM)的临床疗效及安全性.方法 治疗组(24例)口服沙利度胺,同时联合MP方案化疗,每月1个疗程.对照组(22例)单用MP方案化疗,马法兰、泼尼松的剂量和用法同治疗组.在4个疗程后,判断2组疗效及不良反应.结果 治疗组总有效率79....     

硼替佐米联合左旋苯丙氨酸氮芥预处理方案在新诊断多发性骨髓瘤自体造血干细胞移植中的应用

目的探讨硼替佐米联合大剂量左旋苯丙氨酸氮芥(Bor-HDM)为预处理方案在新诊断多发性骨髓瘤(MM)自体造血干细胞移植(ASCT)治疗中的安全性和临床疗效。方法自2016年1月至2019年6月,本中心对18例接受ASCT的新诊断MM患者,应用Bor-HDM作为预处理方案,随访分析移植后反应率及生存情况。并与2012年1月至2016年6月接受左旋苯丙氨酸氮芥预处理的21例MM ASCT患者的治疗反应进行对比研究。结果中位年龄56(27～65)岁。中性粒细胞和血小板植入的中位时间分别为12(10～18)d和15(11～35)d。移植相关非血液学不良反应最常见的为恶心(83%)、呕吐(56%)和腹泻(50%)。移植相关死亡率为0。移植后完全缓解率由22%升至56%。中位随访24(7～38)个月,2年的疾病无进展生存率和总生存率分别为72%和86%。与既往接受HDM组的患者相比,2组患者疾病分型、ISS分期、诱导治疗方案比例差异无统计学意义。HDM组中性粒细胞、血小板细胞植入中位时间分别为11 (9～16)d、16 (9～33)d,2组相比差异均无统计学意义(P=0.092,0.878)。移植后Bor-HDM组完全缓解率高于HDM组(56%与48%,P=0.751)。Bor-HDM组腹泻发生率高于HDM组(50%与24%,P=0.108),余不良反应相似。结论 Bor-HDM方案是MM患者ASCT的安全、有效预处理方案,能否改善患者的长期生存尚待长期随访观察。     

Lenalidomide in combination or alone as maintenance therapy following autologous stem cell transplant in patients with multiple myeloma: a review of options for and against

Introduction: Lenalidomide has multifaceted antimyeloma properties, including direct tumoricidal and immunomodulatory effects. Several randomized controlled trials have demonstrated improved patient outcomes with lenalidomide maintenance after autologous stem cell transplant (ASCT) in patients with newly diagnosed multiple myeloma (NDMM). Currently, single-agent lenalidomide is the only approved post-ASCT maintenance therapy in the United States and European Union for patients with NDMM.

Areas covered: This review article summarizes the efficacy and safety data of lenalidomide maintenance, as monotherapy and in combination with other agents, following ASCT in patients with NDMM. In addition, emerging therapies with newer agents in this setting are discussed.

Expert opinion: Following ASCT, maintenance therapy with lenalidomide until progressive disease is an effective and well-tolerated regimen and represents the standard of care for patients with NDMM. Studies evaluating maintenance with lenalidomide in combination with next-generation proteasome inhibitors, monoclonal antibodies, and histone deacetylase inhibitors may further improve patient outcomes.     

Enriched enrollment: definition and effects of enrichment and dose in trials of pregabalin and gabapentin in neuropathic pain. A systematic review

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Enriched enrolment (the exclusion of non-responders or specific inclusion of responders) is believed to add both to trial sensitivity and to the measured effect of an intervention.
• Enriched enrolment lacks specific definition, and the extent of any differences between results with non-enriched recruitment and enriched enrolment is not known.
• Enriched enrolment is thought to have influenced neuropathic pain trials.

WHAT THIS STUDY ADDS

• The paper suggests definitions for complete and partial enriched enrolment, and applies those definitions to trials of pregabalin and gabapentin in neuropathic pain.
• The effect of enrichment was small, and especially in pregabalin trials with the best data, no difference was found between partial enrichment and no enrichment.
• The effects of complete enrichment are unknown.

AIMS

Enriched enrolment study designs have been suggested to be useful for proof of concept when only a proportion of the diseased population responds to a treatment intervention. We aim to investigate whether this really is the case in trials of pregabalin and gabapentin in neuropathic pain.

METHODS

We defined ‘complete’, ‘partial’ and ‘non-enriched’ enrolment, and examined pregabalin and gabapentin trials for the extent of enrichment and for effects of enrichment on efficacy and adverse event outcomes.

RESULTS

There were no studies using complete enriched enrolment; seven trials used partial enriched enrolment and 14 non-enriched enrolment. In pregabalin trials the maximum extent of enrichment was estimated at about 12%. Partial enriched enrolment did not change estimates of efficacy or harm. Over 150–600 mg maximum daily dose there was strong dose dependence for pregabalin.

CONCLUSIONS

A benefit of partial over non-enriched enrolment could not be demonstrated because the degree of enrichment was rather small, and possibly because enrichment produced little enhancement of treatment effect. Whether a greater degree of enrichment would result in important differences is unknown. Researchers reporting clinical trials with any enrichment must describe both process and extent of enrichment. As things stand, the effects of enriched enrolment remain unknown for neuropathic pain trials.     

多发性骨髓瘤患者外周血造血干细胞动员的临床分析

目的:探讨多发性骨髓瘤(MM)患者使用化疗联合粒细胞集落刺激因子(G-CSF)进行外周血造血干细胞动员的效果及影响因素.方法:将20例MM患者检测采集物中有核细胞数及CD34+细胞数量进行回顾性分析.结果:20例患者共经过44例次单采,自化疗结束至采集日平均时间为10.55(8～14)天.获得有核细胞均数为6.01×108/kg(1.67～14.7×108/kg),CD34+细胞12.49×106/kg(1.9～38×106/kg).仅有2例患者采集物CD34+细胞＜2.5×106/kg.对比两组的临床特征,发现CD34+细胞产率与病程,动员前化疗次数,外周血白细胞恢复时间相关,而与年龄、性别、疾病状态等因素无明显相关性.结论:化疗联合G-CSF方案应用于MM患者中,绝大多数能获得足够的干细胞,对于病程长,化疗次数多动员后血象恢复时间长的患者效果不佳.     

Population pharmacokinetics of melphalan in paediatric blood or marrow transplant recipients

AIM: To develop a population pharmacokinetic model for melphalan in children with malignant diseases and to evaluate limited sampling strategies for melphalan. METHODS: Melphalan concentration data following a single intravenous dose were collected from 59 children with malignant diseases aged between 0.3 and 18 years. The data were split into two sets: the model development dataset (39 children, 571 concentration observations) and the model validation dataset (20 children, 277 concentration observations). Population pharmacokinetic modelling was performed with the NONMEM software. Stepwise multiple linear regression was used to develop a limited sampling model for melphalan. RESULTS: A two-compartment model was fitted to the concentration-vs.-time data. The following covariate population pharmacokinetic models were obtained: (i) Clearance (l h(-1)) = 0.34.WT - 3.17.CPT + 0.0377.GFR, where WT = weight (kg), CPT = prior carboplatin therapy (0 = no, 1 = yes), and GFR = glomerular filtration rate (ml min(-1) 1.73 m(-2)); (ii) Volume of distribution (l) = 1.12 + 0.178.WT. Interpatient variability (coefficient of variation) was 27.3% for clearance and 33.8% for volume of distribution. There was insignificant bias and imprecision between observed and model-predicted melphalan concentrations in the validation dataset. A three-sample limited sampling model was developed which adequately predicted the area under the concentration-time curve (AUC) in the development and validation datasets. CONCLUSIONS: A population pharmacokinetic model for melphalan has been developed and validated and may now be used in conjunction with pharmacodynamic data to develop safe and effective dosing guidelines in children with malignant diseases.     

New generation pharmacotherapy in elderly multiple myeloma patients

Background: Observational databases have demonstrated that the overall prognosis of multiple myeloma patients has markedly improved over the past decade, yet the greatest strides have been attained in younger rather than older patients. Objective: To review recent clinical trials that include new generation agents (thalidomide, lenalidomide and bortezomib) and autologous stem cell transplantation in older multiple myeloma patients. Results: Conventional regimens such as melphalan plus prednisone can be improved with the addition of thalidomide or bortezomib: more patients attain complete and near-complete remission, and progression-free survival rates are nearly doubled. In addition, autologous hematopoietic stem cell transplantation studies show that this treatment approach can be used successfully in selected older myeloma patients in whom the toxicity profile of autotransplant and resulting overall survival may be similar to that obtained in the younger patient group. Conclusions: In the advanced-age population, implementation of new therapies results in significant benefits in older as well as younger patients.     

High-dose cyclophosphamide in multiple sclerosis patients undergoing autologous stem cell transplantation

High-dose cyclophosphamide (CTX) is commonly used in preparation for autologous and allogeneic stem cell transplantation. CTX is a pro-drug, which undergoes complex oxidative metabolism with the metabolites being eliminated both renally and hepatically. In the following study, we evaluated the pharmacokinetic characteristics of high-dose CTX in three patients undergoing autologous stem cell transplantation for multiple sclerosis. The plasma concentration-time profiles for CTX and its hydroxy-metabolite were similar in multiple sclerosis patients to those reported in cancer patients undergoing stem cell transplantation. There was an increase in drug clearance after the second CTX dose indicating that the drug induced its own metabolism consistent with reports in other populations receiving high-dose CTX. One of the three patients cleared the drug slowly but this was not associated with greater toxicity. The patient with the slow clearance value and therefore highest drug exposure had stable disability scores at 2 years posttransplant compared with baseline values taken prior to transplantation. In conclusion, in this small case series, there was no indication that CTX metabolism was different than that in other populations undergoing transplantation.     

Population pharmacokinetics of oral high-dose busulfan in adult patients undergoing hematopoietic stem cell transplantation

Background and the purpose of the study

Many factors have been reported that contribute to the wide intra- and inter-patient variability of Busulfan (Bu) disposition. The purpose of this study was to develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics (PK) of Bu in Iranian adult patients who received oral high-dose as a conditioning regimen before Hematopoietic Stem Cell Transplantation (HSCT).

Methods

A population PK analysis was performed in 30 patients who received an oral Bu and cyclophosphamide regimen before HSCT. Bu was given orally according to the protocol of the institution. In order to prevent seizures caused by Bu, phenytoin was administered orally one hour before each dose of Bu.A total of 180 blood samples were analyzed by HPLC and PK parameters were estimated by the non-linear mixed effect model by MONOLIX 3.1 program. A one-compartment model with an additive error model was used to describe the concentration-time profile of Bu.

Results

Patients’ disease and weight was found to be the determinant factors for clearance (CL) and the volume of distribution (Vd) according to Monolix analysis. The covariate entered in final model followed by these equations:CL = 13.4[1 + (0.141 × Disease)],  Vd = 42.6[1 + 0.010 × (Weight - 63.9)] In this limited study, the age (15–43 years) had no significant effect. For a patient weighting 60 kg, the typical CL and Vd were estimated to be 13.4 l/hr and 42.6 L, respectively. The interindividual variability of CL and Vd were 13.6 and 6.3%, respectively. There was no significant metabolic induction in these four days as is evident by comparing the trough levels of Bu. However it should be mentioned that, one tailed t-test p-values of the days of two and three, two and four and three and four were 0.083, 0.069 and 0.388, respectively.

Major conclusions

Results of this study showed that the type of disease was a determinant of CL and the weight of patient was a determinant of Vd for Bu population PK parameters. A reliable PK parameters and Css, estimated from only one plasma concentrations (5 hrs after the first dose), were validated. Since these methods require few sampling and are easy to be used, the limited sampling methods might be advantageous in the routine clinical practice.     

三次造血干细胞移植治疗多发性骨髓瘤二例临床观察

目的初步探讨三次造血干细胞移植治疗多发性骨髓瘤的安全性及疗效。方法对我院2例多发性骨髓瘤患者三次造血干细胞移植的临床资料进行回顾性分析。2例自体干细胞动员方案均为环磷酰胺(CTX)联合粒细胞刺激因子(G-CSF),采用以马法兰和(或)硼替佐米为主的预处理方案。其中1例第3次为异基因外周血干细胞移植,余均为自体外周血干细胞移植。结果 2例患者三次造血干细胞均成功植入,无移植相关死亡。结论三次造血干细胞移植治疗多发性骨髓瘤安全、有效、可行。     

多发性骨髓瘤患者血栓弹力图检测的临床意义

目的：探讨血栓弹力图（TEG）对多发性骨髓瘤患者体内凝血状态的应用效果。方法：对24例多发性骨髓瘤患者于进行TEG测定,了解其凝血功能情况。结果：患者TEG表现为高凝图像,Angle值、CI值较诈常对照组明显增高（P〈0．05）。结论：多发性骨髓瘤患者体内存在病理性高凝状态,应用TEG动态观察多发性骨髓瘤患者凝血状态,对病情评估及指导治疗有重要意义。     

沙利度胺治疗多发性骨髓瘤的临床疗效

目的 :探讨沙利度胺治疗多发性骨髓瘤 (MM)的临床有效性。方法 :初治、难治或复发MM患者 10例 ,沙利度胺起始剂量 5 0～ 2 0 0mg·d-1,每 2wk增加 5 0～ 2 0 0mg·d-1,直到患者能够耐受或有效 ;同时联合应用化疗。根据M蛋白评定疗效为完全缓解 (CR)、很好的部分缓解 (VGPR)、部分缓解 (PR)、微小反应 (MR)和无反应 (NR)。同时对贫血、骨髓浆细胞比例和其他如口腔溃疡等进行评价。结果 :CR 3例 ,VGPR 3例 ,PR 4例。平均随访时间 5 0 5wk ,总生存率 90 %,无病生存率 30 %。无不能耐受的不良反应。结论 :沙利度胺可作为初发或难治MM的治疗。     

Population pharmacokinetics of pregabalin in healthy subjects and patients with post-herpetic neuralgia or diabetic peripheral neuropathy

AIM

Pregabalin, a chemical analogue of the mammalian neurotransmitter γ-aminobutyric acid, has been approved in many countries for partial-onset seizures, generalized anxiety disorder and various other pain disorders, including neuropathic pain associated with post-herpetic neuralgia and diabetic peripheral neuropathy and fibromyalgia. The aim of this study was to develop a population pharmacokinetic model and quantify the influence of covariates on the parameters.

METHODS

This pregabalin population pharmacokinetic analysis was conducted on data from 14 clinical trials involving healthy subjects, subjects with impaired renal function and patients with post-herpetic neuralgia or diabetic peripheral neuropathy (n = 616). The data analysis was performed using nonlinear mixed effects modelling methodology as implemented by NONMEM.

RESULTS

A one-compartment model with first-order absorption and elimination adequately described pregabalin pharmacokinetics. The model indicated that pregabalin apparent clearance (CL/F) was proportional to estimated creatinine clearance (CL_cr). The pregabalin systemic exposure in patients with lower renal function who received pregabalin 150 mg twice daily was almost equal to that of patients with normal renal function administered pregabalin 300 mg twice daily. The systemic exposure stratified by lower or normal renal function was similar between patients with post-herpetic neuralgia and diabetic peripheral neuropathy.

CONCLUSION

The developed model identified CL_cr and ideal body weight as clinically influential covariates on CL/F and volume of distribution, respectively. This study indicates that renal function accounts for variability in the apparent clearance of pregabalin which is consistent with what is known about the elimination of this drug.     

普瑞巴林治疗带状疱疹后神经痛的临床观察

目的:观察普瑞巴林治疗带状疱疹后神经痛(post-herpetic neuralgia,PHN)的有效性和安全性。方法:52例PHN患者随机分为两组,对照组(n=26)采用传统药物治疗,治疗组(n=26)采用普瑞巴林,剂量从150 mg·d-1起,根据服药后患者疼痛的缓解程度以及不良反应予以调整,疗程4周。采用数字疼痛评分量表(NRS)评估用药前及第1,2和4周的疼痛程度。结果:两组用药后NRS评分均降低,普瑞巴林组治疗后1,2和4周的NRS评分明显低于对照组。普瑞巴林组不良反应较少且轻微,主要表现为头晕和嗜睡。结论:普瑞巴林治疗带状疱疹后神经痛有效且安全。     

普瑞巴林用于糖尿病痛性神经病变的疗效和安全性

目的:研究普瑞巴林用于糖尿病痛性神经病变的疗效和安全性。方法:52例糖尿病痛性神经病变患者随机分2组,对照组服用羟考酮控释片,试验组服用普瑞巴林胶囊,用药2周。评估治疗前后疼痛缓解程度和不良反应的发生情况。结果:对照组和试验组的有效率分别为56.0%和77.8%(P<0.05),试验组的镇痛效果优于对照组。治疗期间未见严重并发症。结论:普瑞巴林治疗糖尿病痛性神经病变疼痛安全有效。     

多发性骨髓瘤肾功能损害的临床分析

目的观察多发性骨髓瘤（MM）肾功能损害的临床特征及相关因素。方法对明确诊断的MM肾功能损害患者的临床特征及实验室检查进行回顾性分析。结果 MM肾功能损害的总发生率为48.28%,以慢性肾功能不全最常见。MM有肾损害与无肾损害患者比较,高钙血症、高尿酸血症、尿本周氏蛋白、骨髓浆细胞数量与肾功能损害之间有相关关系（P〈0.05）。结论老年MM病人以及有高尿酸血症、高钙血症、尿本周氏蛋白阳性、骨髓浆细胞数量高（〉50%）的MM患者更易发生肾功能不全。     

小剂量硼替佐米联合化疗治疗4例多发性骨髓瘤的疗效

目的观察小剂量硼替佐米联合化疗治疗复发难治或初发多发性骨髓瘤（MM）的疗效和不良反应。方法4例MM患者接受硼替佐米＋环磷酰胺＋地塞米松＋沙利度胺治疗,每3周为一疗程。所有患者接受2～4疗程的治疗。采用EBMT疗效标准评价疗效,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4例MM患者中1例接近完全缓解,3例部分缓解。不良反应有白细胞减少、血小板减少、肺部感染等。结论小剂量硼替佐米联合化疗可作为复发难治或初发MM的治疗选择。     

舍曲林联合普瑞巴林治疗老年带状疱疹后神经痛镇痛疗效的研究

目的评价舍曲林联合普瑞巴林治疗老年带状疱疹后神经痛的临床疗效。方法 60例老年带状疱疹后神经痛患者随机分为对照组(n=32)和试验组(n=28)。对照组用普瑞巴林150 mg·d-1,试验组在对照组基础上加用舍曲林50mg·d-1,2组均常规营养神经药物治疗及物理治疗。治疗前、治疗后4周用视觉模拟评分(VAS)评估患者的疼痛强度变化,中文版简明健康测量量表(SF-36)评定生活质量的变化。结果 2组治疗后疼痛强度均较治疗前显著降低(P<0.05),试验组疼痛缓解显著高于对照组(P<0.05)。试验组在6个领域的生活质量较对照组明显改善(P<0.05)。2组不良反应发生率差异无统计学意义。结论舍曲林联合普瑞巴林能提高老年带状疱疹后神经痛的疗效。     

多发性骨髓瘤1557例误诊资料分析

目的通过分析1557例多发性骨髓瘤（MM）误诊资料,总结MM误诊原因、误诊疾病种类及减少误诊的措施。方法查阅2000至2008年有关MM误诊分析的文献164篇,筛选出资料完整,统计比较确切的49篇进行分析。结果初诊MM2389例,其中误诊患者1557例,误诊率为65.17%。主要误诊为6大类疾病,包括骨关节疾病（39.82%）,其中误诊为骨质疏松最多,其次为椎间盘突出、骨折、腰肌劳损、骨质增生;肾脏疾病（15.67%）,主要为慢性肾炎,其次为慢性肾功能不全;血液病（9.38%）;各类感染（7.58%）;心脏疾病（3.60%）;慢性肝病（1.86%）。MM误诊客观原因为临床表现多样,首发症状千差万别,且骨髓瘤细胞往往分布不均,有些患者需经过反复多次、多部位骨穿才能明确诊断;主观原因为临床医师对其认识不够,接诊医生问诊、体格检查不够详细,对实验室检查结果不能正确分析。MM往往引起多器官系统损害,很多医生将其并发症作为早期的诊断。结论加强对MM的全面认识,详细的询问病史,认真细致的体格检查,进行全面的实验室及影像学检查是防止误诊的关键。