DVd(T)方案治疗多发性骨髓瘤17例临床疗效分析

目的:观察脂质体阿霉素(PLD)联合长春新碱(VCR)、地塞米松(Dex)士沙利度胺(Thal)治疗多发性骨髓瘤(MM)患者的疗效及毒副反应.方法:17例初治或复发难治MM患者接受DVd(PLD 40 mg·m-2d1、VCR 2 mg d1、Dex 40 mg d1～4)或DVdT(PLD及VCR用法用量同上,Dex:40 mg,d1～4、d9～12;Thal:100 mg,d1～21)治疗,按照EBMT标准评价疗效、WHO标准判断毒副反应.结果:①17例患者共完成了34个周期的治疗,总有效率(ORR=CR+nCR+VGPR+PR)为58.8%,与国外文献报道接近,与历史上我院采用的VAD及其类似方案相比疗效也接近.②采用DVd方案治疗的11例患者的ORR为4/11(36.4%).其中6例初治患者的ORR为2/6(33.3%).采用DVdT方案化疗的6例患者均为初治病例,其ORR为6/6(100%).对于初治患者.DVdT方案的ORR显著好于DVd方案.③多数治疗相关毒副反应为1～2级且可耐受.17例患者中有13例在接受DVd(T)化疗前心电图或心脏B超示不同程度的心律失常或左室舒张功能降低,但均未因化疗增加心脏毒性.DVd组与DVdT组的毒副反应接近.结论:DVd方案具有较好的耐受性,适当延长Dex用量并加入Thal可以在不增加化疗相关毒性的同时显著提高DVd方案疗效.     

Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs

Therapeutics developed and sold as racemates can exhibit a limited therapeutic index because of side effects resulting from the undesired enantiomer (distomer) and/or its metabolites, which at times, forces researchers to abandon valuable scaffolds. Therefore, most chiral drugs are developed as single enantiomers. Unfortunately, the development of some chirally pure drug molecules is hampered by rapid in vivo racemization. The class of compounds known as immunomodulatory drugs derived from thalidomide is developed and sold as racemates because of racemization at the chiral center of the 3-aminoglutarimide moiety. Herein, we show that replacement of the exchangeable hydrogen at the chiral center with deuterium allows the stabilization and testing of individual enantiomers for two thalidomide analogs, including CC-122, a compound currently in human clinical trials for hematological cancers and solid tumors. Using “deuterium-enabled chiral switching” (DECS), in vitro antiinflammatory differences of up to 20-fold are observed between the deuterium-stabilized enantiomers. In vivo, the exposure is dramatically increased for each enantiomer while they retain similar pharmacokinetics. Furthermore, the single deuterated enantiomers related to CC-122 exhibit profoundly different in vivo responses in an NCI-H929 myeloma xenograft model. The (−)-deuterated enantiomer is antitumorigenic, whereas the (+)-deuterated enantiomer has little to no effect on tumor growth. The ability to stabilize and differentiate enantiomers by DECS opens up a vast window of opportunity to characterize the class effects of thalidomide analogs and improve on the therapeutic promise of other racemic compounds, including the development of safer therapeutics and the discovery of new mechanisms and clinical applications for existing therapeutics.Chirality plays an important role in a variety of disciplines, including pharmaceuticals, foods and flavorings, materials science, and agricultural chemicals. In pharmaceuticals, changing just one chiral center can affect critical compound properties, including potency, off-target side effects, and pharmacokinetics (1–5), thus impacting efficacy and therapeutic index. Since the 1990s, drug molecules originally developed as racemates (a racemate is a 1:1 mixture of two mirror-image compounds or enantiomers) have been separated and developed as single preferred enantiomers (eutomers) because of improved synthesis, purification, and analytical methods. This approach, known as chiral switching, resulted in several new therapeutics based on existing drugs, including esomeprazole (Nexium), escitalopram (Lexapro), levalbuterol (Xopenex), eszopiclone (Lunesta), and levomilnacipran (Fetzima). It also led to new Food and Drug Administration guidance for the characterization and development of stereoisomers (6).There are numerous racemic compounds where chiral switching is impossible, because the chiral center has an exchangeable hydrogen that interconverts on a timescale that is incompatible with storage or dosing of a single pure enantiomer. Some examples of drugs that are still marketed as a mixture of two enantiomers include thalidomide, pioglitazone, bupropion, prasugrel, donepezil, and lorazepam. For each of these molecules, the rate of interconversion of enantiomers under physiological conditions is fast compared with the elimination rate of each molecule.Immunomodulatory drugs derived from thalidomide are an important class of antiinflammatory and antitumorigenic drugs, of which thalidomide is the prototype (7, 8). These compounds (Fig. 1) are all characterized by a nitrogen-substituted 3-aminoglutarimide moiety essential for their therapeutic activity with an exchangeable hydrogen at the chiral center. In addition to thalidomide, a number of analogs, including lenalidomide (Revlimid), pomalidomide (Pomalyst and Imnovid), CC-11006, CC-122, and CC-220, have been or are being developed for the treatment of blood cancers and hematological conditions (e.g., multiple myeloma, myelodysplastic syndrome, lymphoma, and chronic lymphocytic leukemia), solid tumors, and inflammatory diseases (e.g., sarcoidosis, systemic sclerosis, and systemic lupus erythematosus). [We tentatively assign N-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]methyl}cyclopropanecarboxamide (compound 1) as CC-11006, a former development compound for hematological cancers. The chemical structure is disclosed in patents and patent applications related explicitly to this 3-aminoglutarimide (9–11). Experimental data are explicitly disclosed for CC-11006 in the pharmacology review sections for new drug applications (NDAs) 021880 and 204026 corresponding to Revlimid and Pomalyst, respectively. The chemical structure of CC-122 is disclosed in figure 5b in International Patent Application No. WO 2012/125459 (12). The experimental data disclosed in this patent and other patent applications related to the explicit chemical structure (12–16) are also identical to the experimental data in published poster abstracts related to CC-122 (17, 18).]Fig. 1.Structures of thalidomide, pomalidomide, lenalidomide, and protonated and deuterated enantiomers of compound 1 [CC-11006; i.e., (S)-H-1, (R)-H-1, (S)-D-1, and (R)-D-1] as well as protonated and deuterated enantiomers of compound 2 [CC-122; (S)-H-2, ( ...The challenges of dosing and maintaining levels of a single preferred enantiomer of thalidomide analogs are apparent comparing the generally short racemization half-life (rac t_1/2) in human plasma or blood with the longer elimination half-life (elim t_1/2) of thalidomide (19–24) (rac t_1/2 = 2–6 h; elim t_1/2 = 3–8 h), lenalidomide (25–27) (rac t_1/2 < 3 h; elim t_1/2 = 3–8 h), and pomalidomide (28–30) (rac t_1/2 < 1 h; elim t_1/2 = 7.5–9.5 h). The propensity to racemize prior to elimination makes it extremely difficult to assess the properties of the individual enantiomers and impedes mechanistic studies. In fact, the broad spectrum of activity for thalidomide analogs has been extensively studied and suggests multiple target sites of action (7, 31–35). Recently, CC-122 has been defined as a pleiotropic pathway modulator (Celgene Corp) because of its broad range of activity (17, 18). In actuality, each enantiomer may have unique pharmacological and safety profiles. Although there is limited data available and the enantiomers interconvert during the time course of the studies, a few groups have shown that the teratogenicity, in vitro antiinflammatory activity, and in vivo efficacy of protonated thalidomide analogs are caused, in large part, by the (S)-enantiomer (22, 36–38). (S)-pomalidomide was originally advanced into clinical trials as ENMD 0995 (39) but soon abandoned because of the rapid racemization of the exchangeable chiral center (28, 29). Finally, it has recently been shown by X-ray crystallography that the (S)-enantiomers of thalidomide, lenalidomide, and pomalidomide preferentially bind a newly identified target, cereblon (CRBN), believed to be responsible for their efficacy and teratogenicity in a cocrystal with the DDB1–CRBN complex, where DDB1 stands for DNA damage-binding protein 1 (40).Attempts to stabilize the (S)-enantiomer of thalidomide analogs have included replacement of the exchangeable hydrogen with methyl (20, 37, 41, 42) or fluorine groups (43, 44). If and when the stable enantiomer of these analogs was studied, none were superior to the racemic, protonated thalidomide analog. The effects observed included similar or decreased potency, increased degradation, increased toxicity, and/or increased teratogenicity. In vitro stabilization of enantiomers has also been achieved by replacement of the carbonyl group adjacent to the chiral center with an oxetane (45). The impact of this change on in vivo dosing or efficacy has not been reported.Recently, deuterium has been explored to stabilize interconverting enantiomers. Deuterium is a stable isotope of hydrogen with a natural abundance of 0.015%, and it is known for its potential to stabilize chemical bonds. Therefore, deuterium is predicted to not affect the pharmacological properties of a compound, contrary to what can be anticipated with methyl, fluoro, or oxetane functional groups. Furthermore, given the natural abundance of deuterium and its ubiquitous use in past human pharmacokinetic studies, the use of deuterium in therapeutics does not present a safety concern.The use of deuterium to stabilize drugs against undesirable metabolism, known as metabolic switching, began in the 1960s (46–51) and is the predominant approach to deuterated drugs today. Metabolic switching can be a challenging strategy, because it is often difficult to translate from in vitro to in vivo (52), is limited to defined metabolic pathways, and requires the synthesis and testing of numerous analogs.The approach that we describe in this paper, deuterium-enabled chiral switching (DECS), is uniquely differentiated from metabolic switching, in that it is based on chemical stability, is generally independent of metabolism, thus resulting in little or no change in pharmacokinetics, translates from in vitro to in vivo, and requires the synthesis and testing of just two analogs.We are the only group, to our knowledge, to previously and herein report the stabilization and differentiated in vitro and in vivo properties of monodeuterated enantiomers of several thalidomide analogs, including reduced degradation, improved pharmacokinetics, and separation of in vitro antiinflammatory effects (53). Yamamoto et al. (54) previously reported the stabilization of monodeuterated thalidomide enantiomers in aqueous solution but did not differentiate their biochemical properties or their pharmacokinetic and pharmacodynamic properties. Another group has shown improved stability, pharmacokinetics, and separation of in vitro pharmacological effects with pentadeuterated lenalidomide enantiomers (55, 56). However, the latter publications do not differentiate the properties in vivo or allow discrimination of the effects of the additional four deuteria on the 3-aminoglutarimide ring and their pharmacodynamic contributions (55, 56).Herein, we report the synthesis, in vitro characterization, and differentiation of stabilized enantiomers of two unique thalidomide analogs, compounds 1 (57) and 2 (CC-122) (58), and for the first time to our knowledge, we differentiate stabilized enantiomers of thalidomide analogs in in vitro and in vivo efficacy models.     

环孢素A联合沙利度胺治疗骨髓增生异常综合征对T细胞亚群影响的初步研究

为探讨环孢素A联合沙利度胺治疗骨髓增生异常综合征对T细胞亚群的影响,我们对2007年6月至2012年6月我院血液内科门诊和住院低中危MDS患者22例,在给予环孢素A联合沙利度胺治疗前后,应用流式细胞仪对于患者和健康志愿者外周血标本进行T淋巴细胞亚群检测。我们发现:CD4+T细胞在MDS患者外周血的百分比低于正常对照组(P<0.05),CD4/CD8比值与正常对照组相比有显著性差异(P<0.05)。治疗显效组患者治疗后的CD4+T细胞百分率增高(P<0.05),CD8+T细胞百分率减低(P<0.01),CD4/CD8比值在治疗前后有显著性差异(P<0.05)。在治疗前,无效组和显效组在T细胞总数百分率,CD4+T、CD8+T细胞百分率以及CD4/CD8的比值均有统计学意义(P<0.05)。由此我们认为,MDS患者存在T淋巴细胞亚群免疫失调,细胞免疫功能紊乱。CsA以及沙利度胺治疗MDS的机制可能与Th,Ts细胞比率改变有关。     

沙利度胺在口腔黏膜病临床治疗实践中的安全性分析

沙利度胺诞生至今已经超过60年,目前广泛应用于炎症性疾病和自身免疫性疾病的治疗,包括多种口腔黏膜疾病的治疗。由于沙利度胺曾造成严重的致畸不良事件,所以较多医生对其在临床具体应用过程中的安全性尚存在一些疑问和顾虑。本文通过回顾分析有关沙利度胺的药物代谢动力学、药物作用机制以及临床治疗试验研究的文献,着重探讨沙利度胺的药物安全性、对育龄期患者的影响以及对儿童患者的影响等问题,以期为口腔黏膜病科医生提供更为全面的信息,确保其安全有效的应用。     

单疗程沙利度胺联合CTOD方案治疗多发性骨髓瘤22例

目的评价沙利度胺联合CTOD(环磷酰胺、吡柔比星、长春新碱、地塞米松)化疗方案治疗多发性骨髓瘤22例的疗效和不良反应。方法22例患者均给予小剂量沙利度胺联合化疗,沙利度胺的剂量为50～200mg/d,环磷酰胺(CTX)500～600mg/m2×1d,吡柔比星(THP)20mg/m2×(2～3)d;长春新碱(VCR)2mg/m2×1d,地塞米松(Dex)10～15mg/m2×(5～7)d;每2～3月重复,有效可继续化疗2～4次。结果患者一疗程总有效率为90.90%(完全缓解率为4.54%,部分缓解率86.36%),主要不良反应为骨髓抑制,白细胞和血小板分别在化疗后第5～12天、第5～14天降到最低值,外周血象一般在11～15d恢复正常。不良反应不明显,无1例患者因化疗发生不良反应而死亡。结论沙利度胺联合CTOD化疗方案治疗多发性骨髓瘤的较理想方案。     

沙利度胺对大鼠子宫内膜异位症模型血管生成的影响

目的探讨沙利度胺（thalidom ide,THD）对大鼠子宫内膜异位移植物生长和血管生成的影响。方法采用自体移植法建立SD大鼠子宫内膜异位症模型,3周后行剖腹术测量移植物的大小,然后将大鼠随机分为模型对照组（每天腹腔注射生理盐水2mL）,孕三烯酮（YSXT）组（腹腔注射孕三烯酮0.5mg.kg-1.d-1）,沙利度胺3个剂量组（分别腹腔注射5、20、40mg.kg-1.d-1）,联合用药组（腹腔注射孕三烯酮0.5mg.kg-1.d-1,沙利度胺20mg.kg-1.d-1）。4周后再次剖腹评价子宫内膜异位病灶大小和形态学的变化,并通过Ⅷ因子标记异位子宫内膜血管,采用免疫组化法检测异位内膜组织中微血管密度（Microvessel density,MVD）。结果各治疗组异位内膜呈现不同程度萎缩,腺体明显减少,移植物体积均小于模型对照组（P〈0.05）;各治疗组MVD均低于模型对照组（P〈0.05）,其中以沙利度胺40mg.kg-1.d-1剂量组最为明显。结论沙利度胺对大鼠子宫内膜异位病灶有抑制作用,可能是通过抑制血管生成起作用。     

CE-T方案治疗老年难治复发性多发性骨髓瘤的临床研究

目的探讨环磷酰胺联合足叶乙苷化疗（CE）并序贯口服沙利度胺（Thal）治疗老年难治复发性多发性骨髓瘤的临床疗效及相关毒副作用。方法给予13例老年难治复发性MM患者cE方案化疗：环磷酰胺（CTX）300mg／m^2,dl-3;足叶乙苷（VP-16）75mg／m^2,dl-3。每四周重复,化疗间歇期序贯口服沙利度胺50-75mg,2次／d。4-6疗程后根据患者M蛋白、骨髓浆细胞数、血常规、免疫球蛋白、生化等评价疗效及毒副反应。结果CR1例（7.69％）,PR7例（53.85％）,SD3例（23.08％）,PD2例（15.38％）,总缓解率61.54％,且毒副作用较轻。结论CE方案化疗序贯口服沙利度胺疗效确切,毒副反应轻,是治疗难治复发性MM的较为合适的方案,值得临床推广。     

沙利度胺联合GP方案治疗晚期三阴性乳腺癌疗效观察

目的:探讨沙利度胺联合GP方案治疗晚期三阴性乳腺癌的临床疗效及不良反应.方法:对58例晚期三阴性乳腺癌随机分为沙利度胺联合GP方案组(联合组)和GP方案组(化疗组),比较2组的疗效、不良反应、肿瘤标志物及病人生存时间.结果:联合组有效率58.62%,高于化疗组的31.03%(P<0.05),中位生存时间37个月,长于化疗组的32个月(P<0.05);肿瘤标志物下降率65.51%,高于化疗组的37.93%(P<0.05);胃肠道反应率13.79%,低于化疗组的41.38%(P<0.05).2组骨髓抑制、便秘的发生率差异均无统计学意义(P>0.05),其余不良反应不明显.结论:沙利度胺联合GP方案治疗晚期三阴性乳腺癌疗效肯定,不良反应轻,值得临床进一步推广.     

Real‐world health care costs of relapsed/refractory multiple myeloma during the era of novel cancer agents

What is known and objective: High costs of novel agents increasingly put pressure on limited healthcare budgets. Demonstration of their real‐world costs and cost‐effectiveness is often required for reimbursement. However, few published economic evaluations of novel agents for multiple myeloma exist. Moreover, existing cost analyses were heavily based on conventionally treated patients. We investigated real‐world health care costs of relapsed/refractory multiple myeloma in Dutch daily practice. Methods: A retrospective medical chart review was conducted for 139 patients treated between January 2001 and May 2009. Total monthly costs attributable to each cost component were described across all regimens and for bortezomib‐, thalidomide‐ and lenalidomide‐based treatment regimens. Results: Mean monthly total costs (€3,981) varied depending on the sequence of therapy (range: €442–€31,318). Significant cost drivers across all regimens included costs of therapy and hospital admissions. The acquisition costs for novel agents in particular accounted for 32% of mean total monthly costs. Prognostic factors associated with increased mean total monthly costs in multivariate regression analysis included low platelet counts (P = 0·01) and worsening performance status (P < 0·001). Mean total monthly costs of bortezomib‐ and lenalidomide‐based regimens were significantly higher than those for thalidomide‐based regimens in second, third and fourth treatment line. What is new and conclusions: Real‐world costs during treatment of relapsed/refractory multiple myeloma vary greatly. Cost drivers include hospital admissions and acquisition costs of novel agents. Costs also vary by prognostic factors and treatment‐related resource use. Future studies assessing the costs of combination therapy consisting of two or more novel agents are encouraged.