Blood:CLL患者异基因造血干细胞移植:如何进行?何时进行?

2018-06-24 月下荷花 肿瘤资讯

异基因造血干细胞移植(allo-SCT)是高危慢性淋巴细胞白血病(CLL)的治疗选择之一,也是唯一有治愈可能的治疗手段。随着B细胞受体抑制剂(BCRi)BCL2抑制剂的出现,CLL患者的选择和行allo-SCT的合适时机也变得困难。英国Gribben教授在BLOOD杂志上讨论了高危CLL的不同治疗方法,以及新药时代如何使用allo-SCT治疗CLL。

异基因造血干细胞移植(allo-SCT)是高危慢性淋巴细胞白血病(CLL)的治疗选择之一,也是唯一有治愈可能的治疗手段。随着B细胞受体抑制剂(BCRi)BCL2抑制剂的出现,CLL患者的选择和行allo-SCT的合适时机也变得困难。英国Gribben教授在BLOOD杂志上讨论了高危CLL的不同治疗方法,以及新药时代如何使用allo-SCT治疗CLL。

无论何种疾病,拟allo-SCT治疗时需与其他治疗相比较,同时必需权衡风险与获益。根据上述标准,2007年共识明确了需接受allo-SCT的CLL高危患者,包括17p缺失或TP53突变,或嘌呤类似物联合治疗2年内复发/难治者。Allo-SCT是高危CLL唯一治愈性治疗手段。

过去10年中,CLL的治疗发生显着变化。首先,免疫化学治疗代替了化疗,近期BCRi伊布替尼、idelalisib及BCL2抑制剂venetoclax等新药均获得上市批准用于治疗CLL,并且对上述高危CLL高度有效,这也改变了2007年确定的CLL移植标准。因此,在新药可及地区,应重新明确适合移植治疗的CLL患者以及最佳移植时机。

CLL的治疗

CLL是一组异质性疾病,通常疾病进展有症状时才需要治疗。很多因素与预后有关,可预测从诊断到需要治疗的时间,鉴定出需要早期治疗的患者(图1),确定应考虑allo-SCT的患者。CLL8研究显示,年轻患者适合FCR(氟达拉滨+环磷酰胺+利妥昔单抗)免疫化学治疗,生存优于单纯FC化疗。目前,大量研究正在比较免疫化学治疗与新药/新药联合治疗,旨在明确不同风险CLL患者的最佳一线治疗。随着一线治疗结果的改善,既往认为适合移植的难治性疾病必然会明显减少。


图1  CLL预后标志

需评估CLL风险

通常认为,传统治疗并不能治愈CLL,尽管有研究证实免疫球蛋白重链可变区(IGHV)突变时,FCR治疗可获得持续缓解,部分甚至可获得治愈,但多数患者终将复发,需要进行挽救性治疗。因此,应根据疾病特征、治疗反应持续时间或治疗耐受性来评估CLL风险状态。

免疫化学治疗时代干细胞移植的地位

CLL国际工作组定义了CLL难治性疾病,即最后1次抗白血病治疗6个月内治疗失败(疾病稳定、无反应、进展或任何原因导致的死亡)或疾病进展。首次治疗反应持续时间和后续治疗反应是重要的预后因素,末次治疗后早期复发患者为高危。

患者1  56岁男性,Rai IV期CLL,需要治疗。IGHV未突变,12三体,无17p缺失或TP53突变。FCR治疗6周期后,持续血小板减少,微小残留病变(MRD)阳性,FCR结束5个月时疾病进展,细胞遗传学检查发现17p缺失。阿仑单抗治疗后,行减低强度allo-SCT。细胞植入很好,完全供者嵌合,达完全缓解(CR),无GHVD。

免疫化学治疗时代,FCR治疗反应持续6个月被认为结果很差。根据遗传学改变、治疗反应及反应持续时间,CLL划为3个风险组(表1)。低危CLL应包括IGHV突变、β2微球蛋白较低、无11q缺失、无17p缺失/TP53 突变;最高危CLL指TP53缺失/突变、嘌呤类似物难治、免疫化学治疗反应持续时间<24个月且未获CR,此类患者不适合免疫化学治疗,应伊布替尼治疗;高危CLL为标准治疗后复发相对较早,非最高危CLL。

表1  CLL风险分组和相应治疗


患者1为最高危CLL,应优选对TP53缺失/突变或难治性疾病有活性的药物,包括伊布替尼、idelalisib、利妥昔单抗+venetoclax,若不能获取上述药物,则考虑给予allo-SCT治疗。

患者2  46岁女性,CLL伴巨大淋巴结,11q缺失,诊断后18个月疾病进展,给予FCR化疗,耐受良好,获CR。11个月后疾病进展,仍存在11q缺失,无17p缺失或TP53突变,参加临床研究,接受Venetoclax+obinutuzumab治疗,获CR,MRD阴性,进入随访。患者因个人原因不愿行allo-SCT治疗,而且对现有治疗耐受良好,因此继续接受venetoclax治疗,若疾病进展则给予伊布替尼治疗,再行allo-SCT。

患者1和2充分表明,极高危CLL已从仅有allo-SCT治疗时代进入到多种有效治疗可供选择的时代。

新药影响

伊布替尼、idelalisib和venetoclax均对高危CLL有效,包括TP53异常、复发/难治疾病。基于临床研究结果,2014年7月,FDA批准伊布替尼治疗复发/难治CLL、伴17p缺失CLL,2016年3月FDA批准其治疗初治CLL。多数患者伊布替尼耐受良好,副作用可控。

虽然所有CLL均可获益于伊布替尼治疗,但研究显示复发/难治CLL伴TP53突变/缺失时的疗效相对较差,此种极高危患者的24个月无进展生存(PFS)和总生存(OS)分别为63%和75%,仍优于传统化疗。研究的5年随访显示,总治疗反应率89%,初治患者CR率增至29%,复发/难治患者CR率10%,初治患者中位PFS仍未达到,复发/难治伴11q缺失、17p缺失和无IGHV突变患者的中位PFS分别为51个月、26个月和43个月,初治和复发/难治患者5年PFS分别为92%和44%。

Idelalisib和利妥昔单抗已获批用于治疗复发/难治CLL。研究显示,不论是否有TP53途径异常,均不影响治疗活性。对于接受过多次治疗、多为高危疾病的CLL,BCL2抑制剂venetoclax治疗时的治疗反应率达79%。2016年4月,Venetoclax获加速审批治疗复发/难治伴17p缺失CLL。另有3期研究采用Venetoclax+利妥昔单抗治疗2年,苯达莫司汀+利妥昔单抗作为对照,结果显示Venetoclax+利妥昔单抗疗效更优,对伴17p缺失CLL亦有效。因此,极高危CLL已从无药可用时代走向有3种药物可供选择的治疗时代,并且这3种药物可序贯应用也可联合应用。

Allo-SCT在CLL治疗中的地位

目前尚无随机临床研究比较allo-SCT与传统化疗、免疫化疗或新药治疗,也无研究比较清髓移植和减低强度移植的疗效。新药上市必然会影响CLL的allo-SCT选择。欧美国家CLL的allo-SCT病例数目持续下降,而且随着新药的不断出现,这种趋势仍会继续。

首例清髓移植治疗CLL是在20年前,虽然可很好地控制疾病,但死亡率较高,对多数患者并不适用。随后发现非清髓减低强度预处理(RIC)不影响细胞植入和抗肿瘤活性,这就使适合allo-SCT患者增多。有研究显示,RIC  allo-SCT长期疾病控制率40%,能克服TP53异常、氟达拉滨耐药及其他不良预后特征,如SF3B1和NOTCH1基因突变,患者可长期生存,但生存率随时间呈现下降趋势。

17p缺失不影响allo-SCT结果。影响长期PFS的因素包括:既往自体SCT、allo-SCT时未获缓解和供者不匹配。CLL3X研究10年随访显示,allo-SCT10年非复发死亡率20%,PFS34%,OS51%,TP53异常不影响预后,影响复发的因素包括:异基因移植时疾病未能良好控制、采用阿仑单抗去除T细胞,12个月时MRD阴性是复发减低预后因素。

近年,allo-SCT的干细胞来源有较大增加,包括脐血和半相合供者,而且移植效果很好。但随着新药上市,allo-SCT数量仍在不断下降。

Gribben教授如何应用allo-SCT治疗CLL

Gribben教授应用allo-SCT治疗CLL的方法见图2。CLL一线治疗的选择应依据年龄、并发症及是否存在17p缺失/TP53突变选择免疫化学治疗或伊布替尼,有些医师还会考虑是否伴IGHV突变。

基于伊布替尼一线治疗疗效以及venetoclax或idelalisib联合利妥昔单抗挽救性治疗的疗效,Gribben教授不再使用allo-SCT一线治疗伴17p缺失CLL,仅在复发时才会考虑allo-SCT,但需要权衡既往治疗、并发症、治疗反应时间、当前17p缺失/TP53突变状态、其他突变信息如SF3B1和NOTCH1、allo-SCT获益是否能超越副反应和新药疗效,还要比较新药与allo-SCT的费用问题。

Gribben教授推荐,对于复发、具不良预后特征的患者,若一般状态适合allo-SCT,应向相关专家咨询,评估allo-SCT可行性和患者组织类型,确定最佳供者,同胞或家族内供者应行免疫表型分析除外CLL或单克隆B淋巴细胞增生。早期确定供者的意义在于,一旦患者治疗反应差、耐受不佳或新药治疗反应持时短,在疾病可控时可尽早行allo-SCT治疗。

实际工作中,在首次复发时,新药治疗仍可能有效。因此,Gribben教授仍会选择新药,而非直接选择allo-SCT。新药治疗反应持续时间可能较长,即便复发或不耐受也有其它治疗或临床研究可供选择。如果患者接受二线或三线新药治疗且治疗反应很好时,较难判断何时进行移植最为恰当,通常疾病负荷较低时,进行allo-SCT的结果较好。


图2  Gribben教授治疗CLL的流程图

患者3  53岁男性,因血细胞减低、明显淋巴结肿大诊断CLL,淋巴结肿大进展后出现盗汗症状。PET示广泛淋巴结肿大伴低摄取,无高SUV值提示Richter转化,淋巴结活检证实仍为CLL,FISH证实17p缺失。开始伊布替尼治疗,淋巴结肿大迅速缓解,耐受良好。9个月后疾病进展,仍有17p缺失,给予venetoclax治疗。患者有男性同胞供者,在其疾病仍良好控制时决定行allo-SCT。

就移植本身而言,Gribben教授很少采用清髓allo-SCT,仅年轻、进展性或难治性疾病时才会考虑。多数CLL患者身体状态差,清髓allo-SCT增加并发症和死亡率,因此更多采用RIC预处理。确切证据显示,allo-SCT时有移植物抗白血病效应(GVL),因此预处理时不行T细胞去除。Allo-SCT后复发时,供者淋巴细胞输注(DLI)可产生GVL作用,但DLI剂量、输注方案等均无明确推荐,对停用免疫治疗后无GVHD的混合嵌合体,Gribben教授给予低剂量DLI。

有数据显示,allo-SCT后复发时给予伊布替尼治疗,可诱导GVL效应并改善GVHD。疾病复发时亦可给予Venetoclax治疗。

患者1在allo-SCT后3年疾病早期复发,无GVHD证据。Gribben教授先采用伊布替尼治疗,疗效不佳,3个月后停用,给予供者DLI,获CR,目前MRD仍为阴性,有轻度慢性GVHD表现。

Richter转化(RT)是CLL不良结局的风险因素,即便在新药时代,RT治疗仍具挑战性。如果RT患者经传统治疗可挽救,此时进行allo-SCT的结果也比较好。

其他治疗

CLL具有T细胞缺陷,而allo-SCT治疗能诱导T细胞介导的治疗反应,因此可基于这一作用机制治疗CLL,如CAR-T细胞疗法,目前正在研究中。值得注意的是,伊布替尼也能增强T细胞,甚至是CAR-T细胞的功能。CAR-T细胞能否代替allo-SCT或用于无合适供者的CLL仍需进一步研究。

PDL1在CLLT细胞缺陷中具有重要作用,但免疫检查点抑制剂治疗CLL的结果令人失望,不过目前有临床研究正在尝试免疫检查点抑制剂联合治疗对CLL是否有获益。

结语

由于新药疗效好、死亡率低,allo-SCT在CLL中的作用正在下降,但新药能否完全代替allo-SCT仍需进一步研究,或许新药只是延迟了allo-SCT的应用。然而,在不能获得新药或新药不耐受的患者,allo-SCT仍有治疗作用。新药时代,allo-SCT最佳实施时机仍需进一步研究。

原始出处:John G. Gribben. How and when I do allogeneic transplant in CLL. Blood 2018 :blood-2018-01-785998; 

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#插入话题
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  2. [GetPortalCommentsPageByObjectIdResponse(id=1658867, encodeId=4a25165886ee0, content=<a href='/topic/show?id=c40ce798412' target=_blank style='color:#2F92EE;'>#细胞移植#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77984, encryptionId=c40ce798412, topicName=细胞移植)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=ad4724938298, createdName=limedical1982, createdTime=Thu Feb 28 00:06:00 CST 2019, time=2019-02-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1271457, encodeId=3c9c12e145763, content=<a href='/topic/show?id=a0ff950018f' target=_blank style='color:#2F92EE;'>#造血干细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=95001, encryptionId=a0ff950018f, topicName=造血干细胞)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e729101, createdName=huanbaofeng, createdTime=Mon Jun 25 23:06:00 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1287568, encodeId=eaf7128e568f2, content=<a href='/topic/show?id=850849e666e' target=_blank style='color:#2F92EE;'>#异基因造血干细胞移植#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=49766, encryptionId=850849e666e, topicName=异基因造血干细胞移植)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e6ac207, createdName=xlwang2691, createdTime=Mon Jun 25 23:06:00 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1494624, encodeId=0d88149462472, content=<a href='/topic/show?id=084d9499599' target=_blank style='color:#2F92EE;'>#造血#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=94995, encryptionId=084d9499599, topicName=造血)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=caed9138962, createdName=俅侠, createdTime=Mon Jun 25 23:06:00 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=326859, encodeId=2c9a32685928, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Mon Jun 25 09:03:35 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=326617, encodeId=eb2d32661ea5, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Sun Jun 24 11:27:03 CST 2018, time=2018-06-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=326586, encodeId=1e5a32658696, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=92, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0aa31415219, createdName=orangesking, createdTime=Sun Jun 24 10:23:05 CST 2018, time=2018-06-24, status=1, ipAttribution=)]
  3. [GetPortalCommentsPageByObjectIdResponse(id=1658867, encodeId=4a25165886ee0, content=<a href='/topic/show?id=c40ce798412' target=_blank style='color:#2F92EE;'>#细胞移植#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77984, encryptionId=c40ce798412, topicName=细胞移植)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=ad4724938298, createdName=limedical1982, createdTime=Thu Feb 28 00:06:00 CST 2019, time=2019-02-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1271457, encodeId=3c9c12e145763, content=<a href='/topic/show?id=a0ff950018f' target=_blank style='color:#2F92EE;'>#造血干细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=95001, encryptionId=a0ff950018f, topicName=造血干细胞)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e729101, createdName=huanbaofeng, createdTime=Mon Jun 25 23:06:00 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1287568, encodeId=eaf7128e568f2, content=<a href='/topic/show?id=850849e666e' target=_blank style='color:#2F92EE;'>#异基因造血干细胞移植#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=49766, encryptionId=850849e666e, topicName=异基因造血干细胞移植)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e6ac207, createdName=xlwang2691, createdTime=Mon Jun 25 23:06:00 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1494624, encodeId=0d88149462472, content=<a href='/topic/show?id=084d9499599' target=_blank style='color:#2F92EE;'>#造血#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=94995, encryptionId=084d9499599, topicName=造血)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=caed9138962, createdName=俅侠, createdTime=Mon Jun 25 23:06:00 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=326859, encodeId=2c9a32685928, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Mon Jun 25 09:03:35 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=326617, encodeId=eb2d32661ea5, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Sun Jun 24 11:27:03 CST 2018, time=2018-06-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=326586, encodeId=1e5a32658696, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=92, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0aa31415219, createdName=orangesking, createdTime=Sun Jun 24 10:23:05 CST 2018, time=2018-06-24, status=1, ipAttribution=)]
  4. [GetPortalCommentsPageByObjectIdResponse(id=1658867, encodeId=4a25165886ee0, content=<a href='/topic/show?id=c40ce798412' target=_blank style='color:#2F92EE;'>#细胞移植#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77984, encryptionId=c40ce798412, topicName=细胞移植)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=ad4724938298, createdName=limedical1982, createdTime=Thu Feb 28 00:06:00 CST 2019, time=2019-02-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1271457, encodeId=3c9c12e145763, content=<a href='/topic/show?id=a0ff950018f' target=_blank style='color:#2F92EE;'>#造血干细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=95001, encryptionId=a0ff950018f, topicName=造血干细胞)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e729101, createdName=huanbaofeng, createdTime=Mon Jun 25 23:06:00 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1287568, encodeId=eaf7128e568f2, content=<a href='/topic/show?id=850849e666e' target=_blank style='color:#2F92EE;'>#异基因造血干细胞移植#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=49766, encryptionId=850849e666e, topicName=异基因造血干细胞移植)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e6ac207, createdName=xlwang2691, createdTime=Mon Jun 25 23:06:00 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1494624, encodeId=0d88149462472, content=<a href='/topic/show?id=084d9499599' target=_blank style='color:#2F92EE;'>#造血#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=94995, encryptionId=084d9499599, topicName=造血)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=caed9138962, createdName=俅侠, createdTime=Mon Jun 25 23:06:00 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=326859, encodeId=2c9a32685928, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Mon Jun 25 09:03:35 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=326617, encodeId=eb2d32661ea5, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Sun Jun 24 11:27:03 CST 2018, time=2018-06-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=326586, encodeId=1e5a32658696, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=92, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0aa31415219, createdName=orangesking, createdTime=Sun Jun 24 10:23:05 CST 2018, time=2018-06-24, status=1, ipAttribution=)]
    2018-06-25 俅侠
  5. [GetPortalCommentsPageByObjectIdResponse(id=1658867, encodeId=4a25165886ee0, content=<a href='/topic/show?id=c40ce798412' target=_blank style='color:#2F92EE;'>#细胞移植#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77984, encryptionId=c40ce798412, topicName=细胞移植)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=ad4724938298, createdName=limedical1982, createdTime=Thu Feb 28 00:06:00 CST 2019, time=2019-02-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1271457, encodeId=3c9c12e145763, content=<a href='/topic/show?id=a0ff950018f' target=_blank style='color:#2F92EE;'>#造血干细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=95001, encryptionId=a0ff950018f, topicName=造血干细胞)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e729101, createdName=huanbaofeng, createdTime=Mon Jun 25 23:06:00 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1287568, encodeId=eaf7128e568f2, content=<a href='/topic/show?id=850849e666e' target=_blank style='color:#2F92EE;'>#异基因造血干细胞移植#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=49766, encryptionId=850849e666e, topicName=异基因造血干细胞移植)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e6ac207, createdName=xlwang2691, createdTime=Mon Jun 25 23:06:00 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1494624, encodeId=0d88149462472, content=<a href='/topic/show?id=084d9499599' target=_blank style='color:#2F92EE;'>#造血#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=94995, encryptionId=084d9499599, topicName=造血)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=caed9138962, createdName=俅侠, createdTime=Mon Jun 25 23:06:00 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=326859, encodeId=2c9a32685928, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Mon Jun 25 09:03:35 CST 2018, time=2018-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=326617, encodeId=eb2d32661ea5, content=谢谢分享.学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=78, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Sun Jun 24 11:27:03 CST 2018, time=2018-06-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=326586, encodeId=1e5a32658696, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=92, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0aa31415219, createdName=orangesking, createdTime=Sun Jun 24 10:23:05 CST 2018, time=2018-06-24, status=1, ipAttribution=)]
    2018-06-25 明月清辉

    谢谢分享.学习了

    0

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    2018-06-24 明月清辉

    谢谢分享.学习了

    0

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    2018-06-24 orangesking

    0

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