第12届美国血液肿瘤学会年会（SOHO 2024）于2024年9月4日至7日在美国休斯顿举行，汇聚了全球血液肿瘤领域的顶尖专家，交流最新研究成果，探讨治疗新策略。在大会上，美国罗斯韦尔帕克综合癌症中心Eunice Wang教授介绍了Menin抑制剂的最新研发进展。为此，《肿瘤瞭望-血液时讯》特邀采访了Eunice Wang教授，并围绕该话题进行了精彩解读。

《肿瘤瞭望-血液时讯》能否请您分享一下关于Menin抑制剂的最新研究进展？

Eunice Wang教授：在今年SOHO会议上，我分享了关于Menin抑制剂在急性白血病和其他血液恶性肿瘤治疗中的最新进展。目前，我们关于Menin抑制剂的研发已经进入了临床转化的关键阶段，期待其能够获批上市。

FDA将Menin抑制剂作为主要的获批候选药物，这主要基于目前已有的研究数据。数据显示四种不同的Menin抑制剂在既往接受过≥3线治疗的复发或难治性急性白血病（R/R-AL）患者中显示出临床有效性和治疗应答。

在SOHO会议上，我概括总结了这四种Menin抑制剂的当前研究进展，大部分仍处于早期研究阶段，完全缓解率（CR）大约在20%~30%之间，在不桥接异基因造血干细胞移植（allo-HSCT）的情况下，总生存（OS）的获益大约为6~8个月。

Menin抑制剂是首个针对伴有KMT2A（MLL）基因重排或NPM1突变性疾病的靶向治疗，这种患者在新诊断急性髓系白血病（AML）中占5%~30%，因此Menin抑制剂对于很多新诊断或难治性AML的治疗有较大价值。尽管目前显示出的治疗缓解率偏低，但未来我们将继续开展相关研究来探讨Menin抑制剂与其他药物的联合应用，进而将其推向更前线治疗。

Oncology Frontier-Hematology Frontier：What are some of the latest research findings on Megnin inhibitors that you will share in your presentation?

Dr. Eunice Wang：At this year's SOHO meeting, I share the latest updates on Menin inhibitors for the treatment of acute leukemia and potentially other hematologic malignancies. Our research right now has reached a critical point where it's about to be translated, we hope into commercially available drugs.

One of the leading candidates for Menin inhibitor therapy is for USA regulatory approval and that is based on data with up to now four different Menin inhibitors showing clinical efficacy and clinical responses in patients with acute leukemia which have refractory and relapse to up to 3,4,5 lines of therapy.

Overall, I summarize the current progress demonstrated that among these four agents, most of which are still in early testing that there are clinical complete response rates and in the range of 20% to 30% and overall survival benefit in the range of 6 to 8 months in the absence of allogeneic stem cell transplantation.

This is the first targeted therapy for patients with a specific biological disease characterized by KMT2A (MLL) gene rearrangement or by an NPMl mutation. These particular subsets of leukemia make up 5 and 30% of newly diagnosed acute myeloid leukemia cases. So the impact of these inhibitors can be felt on a large proportion of newly diagnosed and refactory acute myeloid leukemia patients. Future research was also discussed and will include to the ongoing clinical trials where these Menin inhibitors with, however, relatively low response rates are now moving into the upfront therapy and the novel combinations.

《肿瘤瞭望-血液时讯》您认为Menin抑制剂将如何改变MDS患者的治疗策略？

Eunice Wang教授：在骨髓增生异常综合征(MDS)患者中，KMT2A重排和NPM1突变的占比并不高。但实验室的数据已经表明，Menin抑制剂对于某些具有特定基因突变的患者也有积极作用，包括含有某些肿瘤驱动基因的AML和MDS患者，例如SF3B1、NOTCH1、ASXL1及MYD88基因突变等。目前，正在开展相关临床试验来探索Menin抑制剂在这些特定亚型的AML或MDS患者是否有临床疗效，若初步结果表明其具有治疗活性，则有进一步开展临床研究的必要性和依据，以探索Menin抑制剂对于MDS患者，尤其是尚未转化为AML的高危MDS患者是否有确切的疗效，我们期待这些研究的结果。但需要指出的是，Menin抑制剂对于其他亚型的AML和MDS患者的疗效并不显著。

Oncology Frontier-Hematology Frontier：How do you think Megnin inhibitors will change the treatment strategies for MDS patients?

Dr. Eunice Wang：MDS patients don't have a high percentage of disease driven by KMT2A rearrangement or by NPM1 mutation. However, there is data in the laboratory that has identified other biological subsets would characterized by specific mutations that may also be positively impacted or inhibited by Menin inhibitors. And these include patients both with AML and MDS characterized by what we think are transcription factor needs driven tumors. These are potentially mutations such as SF3B1, NOTCH1, ASXL1, MYD88. And currently there are ongoing clinical trials investigating whether these  Menin inhibitors may also be of use and induced clinical responses in those particular rotational subsets. If those trials read out that there might be have activity, then it would be quite reasonable to propose future clinical trials, looking at patients with free of leukemia or MDS to see whether this could impact on particularly high risk MDS patients prior to their over transformation to AML.

So we will have to wait and see, but the fact that this could impact additional numbers of patients with both AML and MDS is actually very impaired.

《肿瘤瞭望-血液时讯》您认为Menin抑制剂在未来血液恶性肿瘤治疗研究中有何潜力？

Eunice Wang教授：Menin抑制剂显然在急性白血病中具有良好的疗效，包括KMT2A重排的AML和急性淋巴细胞白血病（ALL）患者。此外，对于除MDS之外的其他突变和特定亚型的血液系统恶性肿瘤，Menin抑制剂同样展现出潜在的治疗前景，携带ASXL1突变的MDS也是潜在的研究对象，目前正在开展相关研究以探索Menin抑制剂是否可用于治疗其他血液恶性肿瘤，例如淋巴瘤。Menin抑制剂在未来可能得到广泛应用。Menin抑制剂针对其支架蛋白Menin的重要作用，可能不仅限于血液恶性肿瘤的治疗，还可能对实体瘤等多种疾病的治疗具有潜在价值，从而为医学研究开辟了广阔的领域。

Oncology Frontier-Hematology Frontier：What do you think is the potential of Megnin inhibitors in future research on the treatment of hematologic malignancies?

Dr. Eunice Wang：Menin  inhibitors apparently seem to have  great impact in acute leukemia is both acute myeloid leukemia, as well as acute lymphocytic leukemia characterized by KMT2A rearrangements. We are hopeful that again, if they are active in other mutation or biological subsets that the benefits of many mutations could also be seen, not only in myelodysplastic syndrome, potentially a myeloproliferative disease that may also be characterized, for example, by ASXL1.

There is ongoing research looking to see whether Menin inhibitor could also be of use in other hematological malignancies like lymphoma. And Menin inhibitors that's being explored more broadly. There are potential implications because of the key role and as a scaffold protein to see whether there might even be solid tumor disease which could be affected by this. So this opens an entirely new field of investigation for us.