编者按：急性髓系白血病（AML）总体治疗效果差，复发难治是其治疗失败的主要原因，目前主要以挽救化疗和造血干细胞移植为主，但该类患者大多数预后仍不理想。因此，亟需新的治疗方案以进一步提高患者生存率及延长生存期。2024年4月14日至17日，第50届欧洲血液和骨髓移植学会（EBMT）年会在英国格拉斯哥隆重举行。在本届大会上，德国德累斯顿大学医院Johannes Schetelig教授就复发难治性AML的治疗进展及挑战做了精彩的专题报告。《血液时讯》特邀请Schetelig 教授走进现场会客室，和广大读者分享有关复发难治性AML治疗策略的真知灼见。

《肿瘤瞭望-血液时讯》:复发难治性AML是临床非常棘手的问题，目前对于该类患者应该采取怎样的治疗策略？

Schetelig教授：复发难治性AML的确是一个复杂的问题。如果我们将治疗后的残余白血病称之为难治性AML时，我们可能会在不同阶段遇到这种情况。从第一个疗程的强化诱导化疗开始，虽然尚未有一个统一性标准将该阶段的耐药AML定义为难治性AML，但至少在我们的研究中提示，它被认为是难治性AML的一个触发因素，尤其在患者具有其他支持进行异基因移植的遗传学特征时。因此，遗传学特征加上早期治疗反应不佳提示患者为高危的AML。对此，我们可以进一步扩展，并将难治性AML定义为经两个疗程的强化诱导后治疗失败的AML，以及在晚期复发时挽救化疗失败的AML。所以，我们所说的复发难治性AML的定义目前不统一。
 

目前对于那些具有高风险遗传学异常的AML患者，我们中心试图减少在进行同种异体造血干细胞移植前的化疗剂量，尽可能温和地将这些患者进行移植，因为我们不太相信诱导移植前的完全缓解（CR）可能使得患者有更好的临床获益。应该说，在移植前诱导CR的原则目前还只是“概念性”的，而不是基于任何前瞻性的随机对照临床试验。我们正在进行的一项临床试验表明，至少诱导CR并不能显著改善患者预后。

My name is Johannes Schetelig. I am Head of the Cell Therapy Unit at the Technical University of Dresden. At the same time, I have the privilege to Chair the Clinical Trials Unit within the DKMS. The question you are asking about relapsed or refractory AML is a complex one, because when we think about residual leukemia after treatment (what we may call refractory AML), then this might be encountered at different stages. Beginning after the first course of intensive induction chemotherapy, at that time, there is not a standard definition to define resistant AML at that stage as refractory AML, but at least in our study group, this is already considered as a trigger, especially when other features support going for an allogeneic transplant. Genetic features plus poor early response indicate that we are dealing with high-risk acute leukemia. But you can also expand this and define refractory AML only as occurring after having failed two courses of intensive induction therapy, or even at the most advanced stage, after a patient has failed salvage chemotherapy in a relapsed setting. This is when we call this relapsed refractory AML. There are multiple ways to define residual or refractory AML. It is most challenging, and I would say dangerous, when morphological leukemia is found after intensive treatment, But, of course, residual  leukemia can also be detected at much lower levels, and then the question is whether or not residual leukemia at the molecular level should also be considered as refractory. Our approach within the Study Alliance Leukemia, which is the large AML study group I belong to, is to distinguish between patients who we aim to cure with chemotherapy alone without allogeneic stem cell transplantation. For those patients, we do think we need dose-intensive chemotherapy, with or without kinase inhibitors in order to improve outcomes (such as midostaurin or other FLT3 inhibitors that may be approved in the next few years in Europe). And then we think of those patients who we identify  as having high-risk genetic abnormalities early on, which render these patients as adverse-risk AML, according to current standard criteria, and for this group of patients, we try to reduce the amount of chemotherapy which we give prior to conditioning for an allogeneic transplantation. The approach is to bring these patients as gently as possible to transplantation, because we are not convinced by the data that suggests that inducing a CR (complete remission) might be beneficial. If you phrase it a little more provocatively, then one should say that the principle to induce a CR prior to transplantation is conceptual, and not based on any prospective randomized clinical trials. We now have the ASAP trial that showed that, at the least, inducing a CR didn’t improve prognosis in a significant way. So we are hesitant to deliver a lot of chemotherapy to those patients where we think, in any way, we need a transplantation.
 

《肿瘤瞭望-血液时讯》:在复发难治性AML患者中，哪些患者适合采用干细胞移植进行治疗？

Schetelig教授：关于干细胞移植的适应证，当涉及到患者年龄时，我们中心并不是十分激进。当患者年龄70岁在以上，我们必须对患者进行非常仔细的评估。当然，有许多70岁以上的患者仍然具有较好的身体状况、具有比较少的合并症，他们是符合异体移植的要求的。但是，总体来说，只有少数75岁以上的患者符合移植的条件；至于80岁以上的患者，我们中心还没有做过这类患者的异体移植。即使在70岁以下，一些患者也可能没有资格接受同种异体移植。其中一些原因可能与白血病相关的并发症，或AML治疗过程中发生的并发症有关。例如，当患者出现器官衰竭时，我们不会考虑移植，严重的慢性肾衰竭是移植的禁忌证，尤其是在肾功能非常差的情况下。
 

另一方面，造血干细胞移植合并症指数（HCT-CI）是一种有助于我们评估患者移植可行性当指标，但它也并不十分完美。许多HCT-CI评分在3以上的患者在我们中心移植后仍然存活。有时尽管HCT-CI评估风险较低，但一些患者可能病情严重。所以，一个好的血液医生应该能够准确评估患者移植的可行性。

《肿瘤瞭望-血液时讯》:哪些临床特征通常预示着患者在移植后能够获得较好的疗效？

Schetelig教授：根据已发表数据和我们中心的经验，AML的遗传生物学特征是患者移植预后的首要预测因素，我们认为它甚至比疾病分期、植前是否存在残留白血病更为重要。对于部分复发的AML患者，他们对于挽救化疗（无论是否使用venetoclax）具有的良好反应，对于这些化疗敏感的患者，他们通常移植预后良好。反而言之，那些携带TP53突变的复杂核型的患者，通常被视为异基因移植后复发的高危人群。对于这类患者，我们需要采用更好的维持治疗策略来降低患者的复发风险。

Based on our interpretation of the published data and our own data, the AML biology is the foremost predictor of outcome after transplantation. We think it is more important than disease stage, and more important than whether or not residual leukemia is present prior to transplantation. There is, of course, a huge range of scenarios. If you think of just patients with de novo AML, these range from patients with relapsed favorable-risk AML, for example, where we do see good responses to salvage chemotherapy, with or without venetoclax, but we definitely often deal with chemo-sensitive disease, and those patients have a very favorable prognosis also after transplantation. The opposite end of the spectrum may be marked by those patients with complex karyotypes harboring TP53 mutations. This is a group of patients where we do have a lot of debate. We are a little more restrictive when it comes to additional comorbidities or additional features that may have an impact on transplant outcome, because, per se, this is a group of patients who you have to envisage as being at high-risk of relapse after allogeneic transplantation. We do need much better maintenance strategies in order to reduce the risk of relapse, especially for this group of patients.

《肿瘤瞭望-血液时讯》:目前可以采取哪些积极的措施来预防移植后的再复发？

Schetelig教授：尽早发现是有效预防复发的关键。事实上，我们应该通过有效的分子标志物来预测所有患者一线治疗后的头两年内的复发风险，以便有足够的时间考虑下一步的治疗策略。这个想法说出来容易，但转化为临床实践很难。但是，在那些通过化疗治愈的大多数患者中，的确发现一些分子标志物适合用于监测微小残留疾病（MRD），例如NPM1突变、核心结合因子（CBF）易位。
 

我们团队在今年的EBMT年会上报告了一项研究，结果显示在没有任何分子复发的情况下进行移植，患者的预后通常会很好。对于复发难治性的患者，经过一、两种甚至更多的强化和挽救性化疗后，情况会更加困难。

不过值得期待的是，一些新的药物有望在欧洲获得批准，例如BCL-2抑制剂对于AML患者的治疗非常具有前景。当然，我们还有其他药物，如FLT3抑制剂，以及IDH1和IDH2抑制剂等等。FLT3抑制剂是一种口服治疗制剂，它的耐受性很好，并且具有非常高的临床获益。基于ADMIRAL和MORPHO两项临床研究数据，我们针对一名FLT3-ITD阳性伴有NPM1突变的AML复发患者，采用Gilteritini进行治疗后获得了客观缓解，这也为我们积极准备移植赢得了时间，然后我们在移植后继续使用这种药物进行维持。

The most important thing to reduce the dangers associated with the risk of relapse is to identify relapse as early as possible. I think that, from now on, we should aim at detecting all relapses that occur in the first two years after first-line treatment by using molecular markers. So relapse should first be detected at a molecular level so there is enough time to think about next treatment steps, and patients should not experience morphological relapse any more. It is easy to say, and hard to translate into clinical practice. There are, of course, some patients who when you try to cure with chemotherapy alone don’t have good markers, but the majority of patients who we attempt to cure with chemotherapy alone do have markers, either NPM1 mutations or core-binding factor (CBF) translocations, which are very suitable for minimal residual disease (MRD) monitoring. I think this is the most important thing to keep in mind - we do have to try to monitor those patients tightly so we identify molecular relapse at an earlier time point. This is something that, again, our group demonstrated at this year’s EBMT - if you transplant those patients without any treatment of the molecular relapse right away, they have an excellent prognosis. When we think of those patients, those patients don’t feel anything from their leukemia. They have a normal blood count. They are suitable to go directly to transplantation. This is something we should aim for in order to improve outcomes. It is much more difficult when we have patients with truly primary refractory disease after one, two or even more lines of intensive and salvage chemotherapy. Then we can be working on new drug combinations, which may get approval in Europe. They probably are approved in other parts of the world already. These are attractive - BCL-2 inhibitors are very attractive for the treatment of acute myeloid leukemia. This is an ongoing field of research. Of course, we have other drugs like FLT3 inhibitors, and IDH1 and IDH2 inhibitors. So, we will get more drugs into our hands in order to safely treat patients, and hopefully to lower the comorbidities associated with treatment. Already now, when we treat patients with FLT3-ITD or FLT3-TKD, we offer FLT3 inhibitors, because we feel this oral treatment is well-tolerated and has a very favorable risk-to-benefit ratio. We offer this to all patients who have approved status for this type of drugs. The hope is that we identify treatments with a favorable risk-to-benefit profile for more patients. When we deal with a patient with relapse of NPM1-mutated AML with FLT3-ITD, we offer gilteritinib, but we don’t wait until complete remission has been achieved. We give it for 3 or 4 weeks. We take the amount of time that we gain with this treatment to organize transplantation, but the aim is still to go for transplantation as soon as possible, and then to continue this effective drug after transplantation. This is building on data that has been produced from the ADMIRAL and MORPHO trials.