[ASCO2016]新药时代造血干细胞移植在骨髓瘤治疗中仍有一席之地?

作者:肿瘤瞭望   日期:2016/6/8 18:53:08  浏览量:41894

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编者按:近年来,多发性骨髓瘤(MM)的治疗在CAR-T、多药联合、免疫治疗方面均取得了突破性的进展。随着新药不断被研发,患者的生存有了大幅度的提高。然而,在这个新药辈出的时代,造血干细胞移植(HSCT)在MM的治疗中是否可以被取代?美国威斯康星医学院Parameswaran Hari 教授在本届ASCO年会上的精彩报告似乎给出了答案。本刊在大会现场特邀请Hari 教授进行了专访。

  异基因HSCT治疗骨髓瘤的适应人群

 

  移植相关的死亡风险是目前异基因造血干细胞移植(alloHSCT)应用于骨髓瘤治疗的主要障碍。相比较而言,自体造血干细胞移植(autoHSCT)及其他药物的治疗风险较小。目前,世界上最好的几家治疗中心报道的alloHSCT相关死亡风险为5%~8%,美国alloHSCT相关的100天总体死亡率已下降到8%。然而尽管如此,患者接受alloHSCT意味着承担不必要风险,除非他们面临着更高的骨髓瘤风险。另一个障碍是,由于大部分骨髓瘤患者的年龄在70岁以上,而对于这样高龄的老年患者通常不适合移植。因此,临床上alloHSCT仅限于较年轻的患者和高危的骨髓瘤患者。

 

  Prof. Hari: The primary obstacle for allogeneic transplants in myeloma is the risk of treatment-related mortality. Allogeneic transplant is a risky treatment. Autotransplant and drugs are lower risk treatment than allotransplant. Allogeneic transplant in even the best centers carries the risk of treatment-related death somewhere between 5% and 8%. In the US, the overall 100-day mortality has come down to 8%. However, this is an unnecessary risk that patients have to face unless they have very high risk from the myeloma itself. That is the primary obstacle. Another is that the majority of patients with myeloma are above the age of seventy and that is an age at which we preferentially don’t do allotransplants because those patients usually don’t do so well. We should be limiting the procedure to younger patients and those at very high risk from the myeloma itself.


  何种情况下骨髓瘤患者优选alloHSCT?

 

  我们的临床实践表明,对于异常高危的骨髓瘤患者通常应用alloHSCT。异常高危的患者意味着患者3年内的死亡率高达50%以上,这些患者通常有以下表现:首先,患有浆细胞白血病,循环浆细胞比例>20%;其次,临床分期Ⅲ期,伴有高危的细胞分子学标志物,或合并乳酸脱氢酶增高;再次,患者自体造血干细胞移植(autoHSCT)后18个月内出现复发。符合以上特征的患者,适合进行alloHSCT。

 

  Prof. Hari:  In our practice, we actually use allogeneic transplant for myeloma in patients that we call ultra-high risk. Ultra-risk means the risk of dying from myeloma is very high, as high as 50% in the first three years. Who are these patients? Firstly, they are patients with plasma cell leukemia with a lot of plasma cells in circulation (20% or more). The second group are those who are stage 3 plus have a high-risk cytogenetic marker. These patients usually have circulating plasma cells and high LDH, which are strong markers of high risk. Thirdly, patients who have relapsed within 18 months of their autotransplant. They get good induction treatment, then get an autotransplant and if they relapse within 18 months, their subsequent survival is very poor. Those are the patients who qualify for allotransplant.

 

  autoHSCT、双次HSCT 和alloHSCT

 

  目前,autoHSCT为骨髓瘤患者的标准治疗方案。在近两年内,我们共完成了四项有关autoHSCT的研究。其中,Palumbo医生和Gay医生分别在NEJM、Lancet Oncology杂志上发表文章,认为早期autoHSCT可以延长患者的总体生存(OS)。另两项研究,Moreau医生在美国血液协会(ASH)年会上进行了报告。今年我们在ASCO大会上呈现了有关IFM2009研究和EMN研究,尽管有关OS的数据还未浮出水面,但均显示出autoHSCT患者的无疾病进展生存(PFS)有明显改善。总之,应尽早地为骨髓瘤患者施行autoHSCT。

 

  关于双次HSCT(tandem autotransplants),在美国并不常做,然在在欧洲许多国家仍然施行这一术式,并且有关的临床数据非常引人注目。在本届ASCO年会上,Cavo医生报告的EMN研究显示,相比较单次autoHSCT和非移植治疗的骨髓瘤患者,几例接受双次HSCT的患者显示出可获得较好的生存的趋势,(尽管是非统计学意义上的分析)。在美国,我们对于首次autoHSCT治疗没有获得完全缓解的患者,不推荐进行双次HSCT;相反,我们会让患者选择进行重复autoHSCT治疗,或者采用来那度胺、地塞米松联合卡非佐米或硼替佐米的联合治疗。

 

  对于alloHSCT,如前所述,我们仅限于对高危(风险在前10%的患者)、较年轻的患者,或者autoHSCT治疗后有早期复发骨髓瘤患者。

 

  Prof. Hari:  I think autotransplant should be standard treatment for anybody who can get it in multiple myeloma. Within the last two years, we have had four studies. Dr Palumbo’s published in the New England Journal of Medicine and Dr Gay’s in Lancet Oncology, both of which showed that patients who went for an early transplant had a longer overall survival. The other two studies were presented by Dr Moreau at ASH, the IFM2009 study, and as presented here at ASCO, the EMN study by Dr Michele Cavo, have shown a longer progression-free survival but are not mature enough to show overall survival. So we have four studies all showing better progression-free survival if patients received a transplant upfront. Autotransplant upfront should be performed on anybody who can receive it based on their age, performance status and their health. To abandon autotransplant is saying that a patient does not need high-dose melphalan and we know that melphalan is a very effective drug against myeloma, so we should always be using autotransplant whenever we can use it. If someone doesn’t receive transplant upfront in the initial treatment, then they should get it later in treatment once they relapse if that occurs. For tandem autotransplants, in the United States, we don’t do too many. But in Europe, many countries still perform tandem autotransplants because the data are very impressive out of Europe. In the EMN study presented here at ASCO by Dr Cavo, several of the patients got tandem autotransplants and they did better, not statistically, but in the survival data, that group was the best followed by the single autotransplants followed by the delayed/no transplant group. In our practice in the US, we restrict tandem autotransplants to people who don’t get to complete remission after their first transplant and then we give them the choice of either a repeat autotransplant or a consolidation treatment like carfilzomib, lenalidomide and dexamethasone or bortezomib, lenalidomide and dexamethasone. As I have said, allotransplant should be restricted to those patients at very high risk, perhaps the top 10% of risky patients i.e. the young patients with plasma cell leukemia, ultra-high risk myeloma or those who have relapsed early after an autotransplant.

 

  在新药年代,是否可延迟HSCT,甚至可以不考虑HSCT?

 

  在本届ASCO年会上,Cavo医生报告的EMN研究回答了这一问题。这项研究纳入了1000例骨髓瘤患者,随机将他们分为autoHSCT组、双次HSCT组和药物治疗组,该研究提示,早期移植可获得较好的PFS。Moreau 医生报告的IFM2009研究具有类似的设计,将患者随机分为硼替佐米、来那度胺和地塞米松诱导治疗+巩固治疗组,以及移植+硼替佐米、来那度胺和地塞米松治疗组,结果表明移植组具有更好的PFS。这两项研究尽管没有OS方面的数据,但

 

  有研究显示早期移植的患者的确可获得更好的OS。

 

  因此,我们认为尽管目前我们有非常有效的新药,如果不进行移植,更确切地说早期移植,患者无法获得更好的生存。未来,随着新药的改进和提升,这一结论也许会被打破。但是从历史上看,自从移植治疗的相关死亡风险被有效控制以来,患者从中的获益远比从药物更新的获益要多得多。因此,我认为未来移植仍在骨髓瘤治疗中具有重要地位。

 

  Prof. Hari: That is the question that has been addressed by Dr Cavo’s study. The EMN study had 1000 patients, one of the largest studies in myeloma, who were randomized to single or tandem autotransplants versus collection of stem cells but no transplant, but continuing on treatment and then everyone on to lenalidomide maintenance. In that study, the patients who had an early transplant benefited in terms of progression-free survival. The IFM2009 study from Dr Moreau had the same design (Velcade, lenalidomide, dexamethasone induction followed by consolidation for patients who did not receive a transplant versus transplant followed by Velcade, lenalidomide and dexamethasone) and the progression-free survival for early transplant was better. We don’t yet know overall survival in those two studies, but we do have studies that show overall survival benefits for early transplant. So skipping transplant, and more specifically, skipping early transplant, is associated with a lower survival, even with novel agents. That may change as the novel agents themselves improve. Having daratumumab and the monoclonal antibodies in the initial therapy may change those results, but historically, when we look at these studies from back in the 1990s, as the initial treatment got better, the benefit of transplant also got proportionately better and better. Transplant as we performed it in the 1990s can be skipped, but autotransplant as we practice now is associated with almost zero treatment-related mortality and excellent benefits, certainly in PFS, and in a couple of studies, overall survival. So it is not yet time to skip transplantation.

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