CN111228264A - 西达本胺联合cgb以及自体造血干细胞的应用及联合药物 - Google Patents
西达本胺联合cgb以及自体造血干细胞的应用及联合药物 Download PDFInfo
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Abstract
本发明涉及药物技术领域，公开了西达本胺联合CGB以及自体造血干细胞的应用及联合药物。本发明提出了对B细胞淋巴瘤具备协同治疗作用的西达本胺联合CGB以及自体造血干细胞移植的治疗方案应用，并通过临床试验验证了西达本胺联合CGB以及自体造血干细胞移植的方案治疗复发或难治性弥漫大B细胞淋巴瘤的PFS和OS分别为81.7％和100％，所述应用能够更高效的治疗B细胞淋巴瘤患者。
Description
本申请要求于2018年11月27日提交中国专利局、申请号为201811427194.8、发明名称为“西达本胺联合CGB以及自体造血干细胞的应用及联合药物”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物技术领域，具体涉及西达本胺联合CGB以及自体造血干细胞的应用及联合药物。
背景技术
B细胞淋巴瘤主要包括弥漫大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、边缘带B细胞淋巴瘤(MZL)、套细胞淋巴瘤(MCL)等。现有利妥昔单抗(R)联合环磷酰胺(CTX)、阿霉素(ADR)、长春新碱(VCR)、强的松(Pred)的R-CHOP方案作为目前弥漫大B细胞淋巴瘤(DLBCL)的标准一线治疗方案，其并取得良好的远期生存。在现有常规免疫化疗下，仍有1/3的患者治疗无效或复发，疗效仍有提高的空间，例如改变常规化疗的组合或增加靶向药物等。高危老年DLBCL患者对于R-CHOP疗效差，CR率仅70％左右，长期生存差，疗效亟待提高。
对于复发及难治患者，化疗仍是挽救治疗的主要手段。二线治疗常用的方案包括与一线方案无交叉耐药，同时对造血影响较小，不影响后续干细胞采集的方案例如DICE，ICE及GemOx方案等进行挽救治疗，但仍有相当部分患者无法得到疾病改善。因此在目前复发或难治性的B细胞淋巴瘤患者，需要探寻更高疗效的解救方案。
长久以来，高剂量联合化疗，如BEAM方案序贯自体造血干细胞移植是复发难治性霍奇金及非霍奇金淋巴瘤的标准治疗方案。然而，在以美罗华为代表的新药参与淋巴瘤治疗的年代，复发后和原发耐药的淋巴瘤患者接受BEAM方案等经典预处理化疗序贯自体移植的疗效受到质疑。例如CORAL研究显示，R-CHOP方案治疗后复发的DLBCL患者，BEAM预处理后自体移植的疗效差于CHOP方案治疗后复发的患者。而且，第一次完全缓解持续时间＜12月，复发时IPI评分大于1分，接受过多种治疗方案，以及移植预处理前仍有活性肿瘤残留者，自体移植效果更差。克拉屈滨/吉西他滨/白消安(CladGemBu，缩写CGB)对多种淋巴瘤细胞有协同细胞毒作用，两个核苷拟似物联合烷化剂增强DNA断裂，诱导细胞凋亡，如何能进一步增强CGB的细胞毒作用，探索和发现新的高效低毒的移植预处理联合用药方案成为值得研究的方向。
发明内容
有鉴于此，本发明的目的在于提供西达本胺联合CGB以及自体造血干细胞在制备用于治疗B细胞淋巴瘤的药物和/或治疗B细胞淋巴瘤中的应用。其中，CGB指本领域中ChiCGB联合用药方案，即克拉屈滨、吉西他滨和白消安的联合药物方案；
本发明所述应用在用于复发的或难治的弥漫大B细胞淋巴瘤时具备突出的治疗效果，在本发明具体实施方式中一线治疗未获得CR或获得CR后复发的弥漫大B细胞淋巴瘤，通过二线/三线获得PR以上疗效者属于复发的或难治的B细胞淋巴瘤患者。
西达本胺(Chidamide，爱谱沙)是我国自主研发的亚型选择性组蛋白去乙酰化酶(HDAC)抑制剂，为1.1类新药。西达本胺的首个适应症——单药治疗复发或难治性外周T细胞淋巴瘤(PTCL)，于2014年12月23日获国家食品药品监督管理总局(CFDA)上市批准，是全球首个该适应症获批上市的口服亚型选择性HDAC抑制剂。西达本胺主要针对第I类HDAC中的1、2、3亚型和第IIb类的10亚型，具有对肿瘤异常表观遗传功能的调控作用。其通过抑制相关HDAC亚型以增加染色质组蛋白的乙酰化水平来引发染色质重塑，并由此产生针对多条信号传递通路基因表达的改变(即表观遗传改变)，进而抑制肿瘤细胞周期、诱导肿瘤细胞凋亡，同时对机体细胞免疫具有整体调节活性，诱导和增强自然杀伤细胞(NK)和抗原特异性细胞毒T细胞(CTL)介导的肿瘤杀伤作用。西达本胺还通过表观遗传调控机制，具有诱导肿瘤干细胞分化、逆转肿瘤细胞的上皮间充质表型转化(EMT)等功能，进而在恢复耐药肿瘤细胞对药物的敏感性和抑制肿瘤转移、复发等方面发挥潜在作用。
西达本胺I期临床试验结果显示，西达本胺单药治疗T细胞型非霍奇金恶性淋巴瘤的有效缓解率达80％，但是入组的3例B细胞型非霍奇金淋巴瘤病人，其中1例经西达本胺治疗后疾病进展，另外2例疾病稳定但都未显示出疗效，上述结果说明西达本胺单药并不具备对于B细胞淋巴瘤的治疗有效性。
然而，本发明出乎意料地发现西达本胺联合CGB以及自体造血干细胞在治疗B细胞淋巴瘤中具有难以想象的超高疗效，采用本发明联合用药策略后，预试验19例可评价患者，中位随访时间为10.3个月(范围3-26.5月)PFS和OS分别为81.7％和100％。
基于此技术效果，本发明根据所提出的应用，具体提供了一种联合药物，其包含用于同时、分别或依次给药的具有有效剂量的西达本胺、克拉屈滨、吉西他滨和白消安，以及用于自体移植的自体造血干细胞。
同时，本发明也提供了一种制备B细胞淋巴瘤的制剂，其以西达本胺、克拉屈滨、吉西他滨、白消安以及自体造血干细胞为主要活性成分，分别或组合添加其他互不影响的活性成分和/或辅料形成的组合制剂。所述其他互不影响的活性成分可以是治疗B细胞淋巴瘤的活性成分，也可以是治疗其他疾病的活性成分或两者的组合。
此外，本发明还提供一种治疗B细胞淋巴瘤的方法，同时、分别或依次给予具有有效剂量的西达本胺、克拉屈滨、吉西他滨、白消安以及自体造血干细胞。
由以上技术方案可知，本发明提出了对B细胞淋巴瘤具备协同治疗作用的西达本胺联合CGB以及自体造血干细胞移植的治疗方案应用，并通过临床试验验证了西达本胺联合CGB以及自体造血干细胞移植的方案治疗复发或难治性弥漫大B细胞淋巴瘤的PFS和OS分别为81.7％和100％，所述应用能够更高效的治疗B细胞淋巴瘤患者。
具体实施方式
本发明公开了西达本胺联合CGB以及自体造血干细胞的应用及联合药物，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明所述应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述应用进行改动或适当变更与组合，来实现和应用本发明技术。
以下就本发明所提供的西达本胺联合CGB以及自体造血干细胞的应用及联合药物做进一步说明。
实施例1：西达本胺、克拉屈滨、吉西他滨、及白消安(ChiCGB)方案联合自体造血干细胞移植治疗复发或难治性弥漫大B细胞淋巴瘤的多中心、单臂、开放性II期临床试验
试验药物：
西达本胺片：类白色片，5mg/片。由深圳微芯生物科技有限责任公司生产。
克拉屈滨：水针剂，10mg/支。由浙江海正药业股份有限公司生产
吉西他滨：采用市售药物。
白消安：水针剂，60mg/支。由大冢制药研发(北京)有限公司生产。
病例数：本临床试验共计划入组93例患者。
入选标准：患者须满足下列全部标准才能入组。
1.一线治疗未获得CR或获得CR后复发的弥漫大B细胞淋巴瘤，通过二线/三线获得PR以上疗效者；
2.肾功能正常(定义为eGFR≥60ml/min/1.73/m2，以及肌酐小于160μmol/L)；肝功正常(定义为ALT及AST≤3倍正常上限；总胆红素≤2倍正常上限)；肺功能正常(定义为FEV1、FVC、DLCO≥50％预测值)心脏功能正常(左室射血分数≥50％，无症状性心律失常)
3.年龄为18-60岁之间，男、女不限；
4.ECOG体力评分0-1分；
5.中性粒细胞绝对值≥1.5×109/L，血小板≥70×109/L，血红蛋白≥90g/L；
6.预期生存时间≥3个月；
7.自愿签署书面知情同意书。
治疗方案：
1、预处理：预处理方案采用西达本胺、克拉屈滨、吉西他滨及白消安(ChiCGB)方案，预处理各药物的给药时间和剂量如下：
西达本胺片，规格：5mg/片。
用法用量：口服，每次服药30mg(6片)，第-7、-4、0、+3天(以自体造血干细胞回输时间为基准(0)，-代表在这之前，+代表在这之后，下同)；
克拉屈滨用法用量：静脉滴注，6mg/m2/天，滴注2小时，第-6至-2天。
吉西他滨用法用量：静脉滴注，2500mg/m2/天，滴注速度10mg/m2/min,第-6、-2天。
白消安用法用量：静脉滴注，3.2mg/kg，滴注3小时，第-6至-3天。
如果实际体重超过理想体重(IBW)20％以上者，应采用校正后理想体重(AIBW)计算药物剂量。
给药顺序：克拉屈滨→间隔4小时→吉西他滨→白消安
2、回输自体造血干细胞。
3、移植期间给予对症支持治疗以及预防病原微生物感染治疗。
4、评价指标和访视
各阶段的评价指标如下表1所示：
表1
肝肾糖脂：谷丙转氨酶(ALT)、谷草转氨酶(AST)、总胆红素(TBIL)、直接胆红素(DBIL)、间接胆红素(IBIL)、谷氨酰转肽酶(GGT)、白蛋白(ALB)；尿素氮(BUN)、肌酐(Cr)；血糖；甘油三脂、胆固醇；乳酸脱氢酶(LDH)采用PET/CT作为评估，疗效评价时选用与基线相同的检测手段。
临床试验结果：预试验19例可评价患者，中位随访时间为10.3个月(范围3-26.5月)PFS和OS分别为81.7％和100％。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (6)
1.西达本胺联合CGB以及自体造血干细胞在制备用于治疗B细胞淋巴瘤的药物和/或治疗B细胞淋巴瘤中的应用。
2.根据权利要求1所述应用，其特征在于，所述B细胞淋巴瘤为复发的或难治的B细胞淋巴瘤。
3.根据权利要求1或2所述应用，其特征在于，所述B细胞淋巴瘤为复发的或难治的弥漫大B细胞淋巴瘤。
4.一种联合药物，其特征在于，包含用于同时、分别或依次给药的具有有效剂量的西达本胺、克拉屈滨、吉西他滨和白消安，以及用于自体移植的自体造血干细胞。
5.一种治疗B细胞淋巴瘤的组合制剂，其特征在于，以西达本胺、克拉屈滨、吉西他滨、白消安以及自体造血干细胞为主要活性成分，分别或组合添加其他互不影响的活性成分和/或辅料形成的组合制剂。
6.一种治疗B细胞淋巴瘤的方法，其特征在于，同时、分别或依次给予具有有效剂量的西达本胺、克拉屈滨、吉西他滨、白消安以及自体造血干细胞。
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| CN112274509B (zh) * | 2020-12-02 | 2022-04-26 | 四川大学华西医院 | 西达本胺联合bcl2抑制剂在双表达型b细胞淋巴瘤中的应用 |
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