摘要：2024年12月7~10日，第66届美国血液学会（ASH）年会在美国圣迭戈隆重召开，全球血液学专家学者齐聚一堂，共同对血液领域最新研究进展进行深入探讨与交流。在本届大会上，加拿大多伦多病童医院Sumit Gupta教授及其团队汇报了AALL1731研究的最新结

编者按：2024年12月7~10日，第66届美国血液学会（ASH）年会在美国圣迭戈隆重召开，全球血液学专家学者齐聚一堂，共同对血液领域最新研究进展进行深入探讨与交流。在本届大会上，加拿大多伦多病童医院Sumit Gupta教授及其团队汇报了AALL1731研究的最新结果（摘要号：1），该研究深入探索了在标准化疗基础上加入Blinatumomab治疗标危组急性B淋巴细胞白血病（B-ALL）患儿的疗效与安全性。为深入了解相关内容，《肿瘤瞭望-血液时讯》特邀采访了Sumit Gupta教授并分享了AALL1731研究的关键发现，现整理如下。

01

《肿瘤瞭望-血液时讯》：能否总结一下AALL1731研究的主要结果？

Sumit Gupta教授：AALL1731是一项美国儿童肿瘤协作组（COG）的随机临床试验，由我和联合主席Rachel Rau博士共同牵头开展。这项研究对所有入组的标危组急性B淋巴细胞白血病（B-ALL）患儿进行了随机分组，这些儿童具有中等或较高的复发风险，我们称之为标危-平均复发风险（standard-risk average）组和标危-高复发风险（standard-risk high）组，随机分配并分别接受标准化疗或标准化疗联合2周期的Blinatumomab治疗。

Blinatumomab是一种免疫制剂，可靶向B细胞表面的CD19并招募患者自身的T细胞来攻击和杀灭白血病细胞。在该研究的第一次中期分析时，数据安全监测委员会终止了这项研究，因为Blinatumomab的疗效结果非常好。例如，仅接受化疗的标危-平均复发风险组患者的3年无病生存率（DFS）达到了90%，而接受化疗联合Blinatumomab的患者，3年DFS则高达97.5%，得到了显著提高。同时，对于标危-高复发风险（standard-risk high）组患者，仅接受化疗的患者3年DFS为85%，但联合Blinatumomab后3年DFS提高到94%。

因此，上述结果表明，对于大多数B-ALL患儿，标准化疗联合Blinatumomab代表了一种新的标准治疗方案，对于仅用化疗无法获得良好或非常良好疗效的B-ALL患儿，推荐接受化疗联合Blinatumomab的治疗方案。

Oncology Frontier-Hematology Frontier：Could you please summarize the main result of the AALL1731 studies ?

Professor Sumit Gupta：AALL1731 was a randomized trial of the Children's Oncology Group, co-led by myself and my co-chair, Dr. Rachel Rau.And what this study did is it took all children with standard-risk B-cell ALL, and those children who were at either an average or a higher risk of relapse, which we call standard-risk average and standard-risk high, were randomized to receive either standard chemotherapy or standard chemotherapy with two cycles of Blinatumomab.

Blinatumomab is an immune agent that targets CD19 on the surfaces of B cells and then recruits the patient's own T cells to attack and kill those leukemia cells. And the study at the first planned interim analysis was shut down by the Data Safety Monitoring Committee because the efficacy results were extremely good with Blinatumomab.So, for example, the standard-risk average group of patients who received chemotherapy alone had a three-year disease-free survival of 90%, whereas those who received chemotherapy and Blinatumomab had a disease-free survival of 97.5%, so quite a substantial increase.And then in parallel, the standard-risk high patients, those at a higher risk of relapse, who received chemotherapy alone had a disease-free survival at three years of 85%, but that increased to 94% with the addition of Blinatumomab.

So these results to us indicate that for most children with B-cell ALL, the addition of Blinatumomab to standard chemotherapy now represents a new standard treatment that most children with ALL who do not already have a favorable and extremely favorable outcome with chemotherapy alone should be treated with chemotherapy plus Blinatumomab.

02

《肿瘤瞭望-血液时讯》：谈一谈Blinatumomab应用时的主要安全性问题，例如神经毒性或细胞因子释放综合征以及不同水平的毒性？

Sumit Gupta教授：非常好的问题，我认为可以分成两部分来回答。一方面，如你所提及的，Blinatumomab确实与某些不良反应（AES）相关，例如细胞因子释放综合征（CRS）和神经毒性。但值得庆幸的是，3级或更高级别的CRS或神经毒性的发生率非常低，大约为1%~3%。需要说明的是，该研究入组的患儿在接受Blinatumomab治疗时疾病负荷非常低，这也会降低不良反应的发生风险。另外一方面，需要注意的是，该研究中入组的患儿年龄均为10岁以下，有部分研究数据显示，在较年长的儿童中，发生神经毒性的风险相对更高，故研究结果需谨慎看待。但在该研究中，CRS和神经毒性非常少见，这一点令人欣慰。

此外值得注意的是，与仅接受化疗的患者相比，接受化疗联合Blinatumomab治疗的标危-平均复发风险（standard-risk average）组的患者，发生3级脓毒症或导管相关感染的风险比较高。有趣的是，这些脓毒症和导管相关感染事件似乎并未发生在Blinatumomab给药期间，而是在随后的化疗周期中风险增加。因此，我们正在进行进一步分析以获取更多的信息，但我们假设这可能与Blinatumomab引起的B细胞缺乏及化疗效应之间的相互作用存在相关性。所幸的是，与仅接受化疗的患者相比，接受Blinatumomab和化疗的儿童发生4或5级严重脓毒症或感染的比例并未增加。

Oncology Frontier-Hematology Frontier：what were the main safety considerations when Blinatumomab is used in syndrome and like neurotoxicity or cytokine release syndrome, for different levels of toxicity?

Professor Sumit Gupta：Yeah, it's a great question. So I think I'll divide the answer into two parts. The first part is, we know, as you referenced, that there are certain side effects that are associated with Blinatumomab, things like cytokine release syndrome (CRS) and neurotoxicity. So thankfully, the rates of grade three or higher CRS or neurotoxicity were very low. It was in the order of one to three percent. Now, I will say that this is a group of children who had very low, very minimal disease burden at the time that they received Blinatumomab, and we know that that has a lower risk of side effects.The other caveat to put there is that these children were all less than 10 years old.And there's a little bit of data out there to show that the risk of neurotoxicity might be higher in older children.So again, take that with a grain of salt. But in this population, those side effects and toxicities were actually thankfully very, very rare.The one thing to note, however, is that we did see a higher risk of grade three sepsis or catheter-related infections in the standard-risk average patients who received chemotherapy and Blinatumomab versus those who received chemotherapy alone.Now the interesting thing about that finding is that those events, those sepsis and catheter-related infection events, didn't really seem to happen during the Blinatumomab administration itself but seemed to be an increased risk in the subsequent chemotherapy cycles.So we're in the midst of doing extra analyses to try to get more information about that, but we hypothesize that that may be an interaction between the B-cell aplasia that you get with Blinatumomab and the effects of chemotherapy.

Thankfully, the rate of grade 4 or grade 5, so serious sepsis or infections, was not increased in children who received Blinatumomab and chemotherapy versus those with chemotherapy alone.

03

《肿瘤瞭望-血液时讯》：是否计划在未来开展新的研究？

Sumit Gupta教授：非常好的问题。正如我提到的，该研究中纳入的是一组NEJM）上的论文探讨了将Blinatumomab应用于30~70岁成人B-ALL患者治疗的疗效，获得了成功结果。严格来说，我们目前尚无关于10~30岁这一中间年龄段患者人群的研究数据。但需要注意的是，至少在北美地区，较年长的B-ALL患儿所应用的治疗主体与我们该研究中的方案相同，因此，我们很难去假设Blinatumomab对于30岁的患者有效，却对10~30岁的中间年龄段患者无效。但毫无疑问，我们需要更多的研究数据来填补这一领域的空白。

更令人兴奋的是，目前已经知道Blinatumomab在预防骨髓相关性复发方面非常有效。那么一个问题是：在Blinatumomab如此有效的情况下，我们是否应减少部分的化疗？我们的这项研究仅是联合了Blinatumomab，并未减少化疗，但我们目前正在设计研究以探讨在减少部分化疗的情况下，是否仍能保持非常良好的治疗效果，同时避免化疗相关的短期和长期不良反应。最后我想说的是，Blinatumomab在中枢神经系统（CNS）中没有活性，因此，尽管我们的研究中CNS复发率非常低，但接受单独化疗和化疗联合Blinatumomab的患者之间，在CNS复发率方面并无差异。因此，未来研究的一个方向将是如何在减少化疗的同时保持治疗效果，并预防部分的CNS复发，而这是Blinatumomab未能实现的。

Oncology Frontier-Hematology Frontier：Do you have any studies planned in the future?

Professor Sumit Gupta：Yeah, it's a great question. So, you know, this population, as I said, was a less-than-10-year-old population, and the results have been published today.So I think that becomes now standard.At the same time, earlier this summer, another New England Journal of Medicine paper was published on the success of adding Blinatumomab to adults aged 30 to 70 years.So technically, we don't yet have data for that in-between population, the 10- to 30-year-olds.But it's important to know that those, at least in North America, older children are treated with the same types of backbones as we studied in this group.And it's difficult to hypothesize that Blinatumomab would work in less-than-10-year-olds and over-30-year-olds, but not work in between.But certainly, you could say that we need more data there.I think the more exciting thing potentially is we know now that Blinatumomab is very effective in preventing bone marrow-related relapses.

So one question is, can we actually start to get rid of some of our chemotherapy?Do we need all that chemotherapy when we have the effectiveness of Blinatumomab in play?Our study just added Blinatumomab, did not take any chemotherapy away, but we're in the midst of now designing studies that will see whether we can maintain these very, very excellent outcomes while taking away some of the chemotherapy and the short- and long-term effects that are associated with that.The last thing I'll say is that Blinatumomab does not have activity in the central nervous system (CNS).And so even though the rate of CNS relapses was very low on our trial, it was not different in the patients who received chemotherapy alone versus chemotherapy plus Blinatumomab.So one area of future study is going to be how we go into this new world with taking away chemotherapy, maintaining outcomes, but also preventing some of the CNS relapses, which Blinatumomab did not do.

来源：肿瘤瞭望