The single-drug therapy provides clinical benefit and could help more patients with hard-to-treat leukemias proceed to stem cell transplant

单一药物治疗提供了临床益处，可以帮助更多难以治疗的白血病患者进行干细胞移植

LBA-5: Revumenib Monotherapy in Patients with Relapsed/Refractory KMT2Ar Acute Leukemia: Topline Efficacy and Safety Results from the Pivotal Augment-101 Phase 2 Study

LBA-5：复发/难治性KMT2Ar急性白血病患者的Revumenib单药治疗：关键的Augment-101 2期研究的一线疗效和安全性结果

SAN DIEGO, Dec. 12, 2023 /PRNewswire/ -- Patients with relapsed or refractory acute leukemia with rearrangement in the lysine methyltransferase 2a gene, a genetic marker known as KMT2Ar, who were treated with revumenib saw an overall response rate of 63%, according to results from a phase II trial being reported during the 65th American Society of Hematology (ASH) Annual Meeting and Exposition.

圣地亚哥，2023年12月12日/PRNewswire/--根据第65届美国血液学会（ASH）年会和博览会期间报告的II期试验结果，接受revumenib治疗的复发或难治性急性白血病患者，赖氨酸甲基转移酶2a基因（一种称为KMT2Ar的遗传标记）发生重排，总有效率为63%。

Revumenib is an experimental, targeted therapy being studied as a treatment for acute leukemias with certain genetic abnormalities. The trial was stopped early due to the high rate of efficacy meeting a prespecified threshold, suggesting that the drug could offer a new and more effective treatment option for patients with rearrangements in the KMT2Ar gene. .

Revumenib是一种实验性的靶向治疗方法，正在研究用于治疗具有某些遗传异常的急性白血病。由于达到预定阈值的高疗效率，该试验提前停止，这表明该药物可以为KMT2Ar基因重排患者提供新的更有效的治疗选择。。

Of study participants whose cancer responded to the treatment, 39% proceeded to a stem cell transplant and half had initiated post-transplant maintenance treatment with revumenib at the time of the data cutoff. Based on these results, researchers say revumenib provides a promising avenue to allow more patients to proceed to a stem cell transplant, the only known curative treatment for aggressive and hard-to-treat KMT2Ar cancers..

在癌症对治疗有反应的研究参与者中，39%进行了干细胞移植，一半在数据截止时开始了用revumenib进行移植后维持治疗。基于这些结果，研究人员表示，revumenib为更多患者进行干细胞移植提供了一条有前途的途径，干细胞移植是唯一已知的治疗侵袭性和难治性KMT2Ar癌症的治疗方法。。

'Any time you have relapsed or refractory acute leukemia, the only cure is transplant, but to do that, you have to have a response,' said Ibrahim Aldoss, MD, associate professor in the Department of Hematology and Stem Cell Transplant at City of Hope National Medical Center, the study's lead author.

该研究的主要作者、希望之城国家医学中心血液学和干细胞移植系副教授、医学博士易卜拉欣·奥尔德斯（IbrahimAldoss）说，无论何时复发或难治性急性白血病，唯一的治疗方法就是移植，但要做到这一点，你必须有反应。

'We observed encouraging durable and meaningful responses, and many of these patients were able to proceed successfully to transplant. We have not seen this level of activity with any other available treatment in this advanced disease setting.'.

“我们观察到令人鼓舞的持久和有意义的反应，其中许多患者能够成功进行移植。在这种晚期疾病环境中，我们还没有看到任何其他可用治疗方法的这种活性水平。”。

The KMT2Ar genetic abnormality is found in about 10% of acute leukemias and can occur in several types of leukemia in both children and adults. KMT2Ar acute leukemia is exceptionally hard to treat, with most patients relapsing after chemotherapy and transplant. In adults, remission rates after relapse and median overall survival remain low.

KMT2Ar基因异常在大约10%的急性白血病中发现，并且可以在儿童和成人的几种类型的白血病中发生。KMT2Ar急性白血病极难治疗，大多数患者在化疗和移植后复发。在成人中，复发后的缓解率和中位总生存率仍然很低。

Revumenib is a small molecule drug that targets the pathway that is instrumental in the expression of the KMT2A-rearranged driven leukemia with a goal of counteracting its effects. An earlier phase I trial had established the drug's safety and appropriate dosing strategy..

Revumenib是一种小分子药物，其靶向有助于表达KMT2A重排驱动的白血病的途径，目的是抵消其作用。早期的I期试验已经确定了该药物的安全性和适当的剂量策略。。

For the phase II trial, researchers administered revumenib orally to 94 patients, both pediatric and adult, with relapsed or refractory KMT2Ar acute leukemias in 28-day cycles. Most (83%) had acute myeloid leukemia and the rest had acute lymphoblastic leukemia or mixed phenotype acute leukemia. All participants had received previous cancer treatments, but their cancer had either not responded to or had come back after the initial treatments; about half had previously received a stem cell transplant..

对于II期试验，研究人员在28天的周期内对94名儿童和成人复发或难治性KMT2Ar急性白血病患者口服revumenib。大多数（83%）患有急性髓细胞白血病，其余患有急性淋巴细胞白血病或混合表型急性白血病。所有参与者都曾接受过癌症治疗，但他们的癌症要么没有反应，要么在初始治疗后复发；大约一半以前接受过干细胞移植。。

An interim analysis of the drug's efficacy was conducted on 57 participants with centrally confirmed KMT2Ar, and performed six months after the last of these patients enrolled, a timepoint selected to allow sufficient time for response to the drug to take place. This analysis revealed that the best responses, defined as a complete response or complete response with hematologic recovery (meaning the cancer is gone and blood cell counts have returned to normal or adequate levels) occurred in 23% of patients.

对57名中央确诊的KMT2Ar患者进行了药物疗效的中期分析，并在最后一名患者入选后6个月进行，选择该时间点以留出足够的时间对药物产生反应。该分析显示，23%的患者发生了最佳反应，定义为血液学恢复的完全反应或完全反应（意味着癌症已经消失，血细胞计数已经恢复到正常或足够的水平）。

That proportion exceeded the prespecified threshold for efficacy, so the trial was stopped early..

该比例超过了预先设定的疗效阈值，因此试验提前停止。。

Among the 36 patients who attained a response, 25 were characterized as having a complete response, meaning that fewer than 5% of marrow cells were cancerous as seen under the microscope. Of these 25 patients, 22 had testing at their institution for measurable residual disease (MRD), another marker that indicates the depth of cancer eradication, and 15 (68%) achieved MRD-negativity..

在36名获得反应的患者中，有25名被表征为完全反应，这意味着在显微镜下观察到不到5%的骨髓细胞是癌细胞。在这25名患者中，有22名在他们的机构进行了可测量残留病（MRD）的检测，这是另一种指示癌症根除深度的标志物，有15名（68%）达到了MRD阴性。。

'A majority of responders achieved MRD-negative status, which is a deep remission, indicating that these patients responded exceptionally well to the treatment,' said Dr. Aldoss. 'The results demonstrate that targeting the menin protein in leukemias with KMT2Ar genetic abnormality results in clinical benefit for patients, regardless of patients' age, and this benefit was observed across different KMT2Ar leukemia [types].'.

奥尔德斯博士说：“大多数应答者达到MRD阴性状态，这是一种深度缓解，表明这些患者对治疗反应异常良好。”结果表明，针对具有KMT2Ar遗传异常的白血病中的menin蛋白，无论患者的年龄如何，都会对患者产生临床益处，并且在不同的KMT2Ar白血病[类型]中观察到这种益处。

Treatment-related adverse events occurred in 82% of patients, the majority of which were manageable, according to Dr. Aldoss. Nausea, differentiation syndrome (a group of symptoms indicating a reaction to cancer treatment in which cancer cells mature to become normal cells), and reversible QTc prolongation (a measure of effects on the heart electricity waves) were the most common.

据Aldoss博士称，82%的患者发生了与治疗相关的不良事件，其中大多数是可控的。恶心，分化综合征（一组症状表明对癌症治疗的反应，其中癌细胞成熟为正常细胞）和可逆QTc延长（对心脏电波的影响的量度）是最常见的。

About half of patients experienced treatment-related adverse events of grade three or higher. Data showed 6.4% of patients discontinued the therapy as a result of adverse events, with no patients discontinuing due to differentiation syndrome or QTc prolongation. .

大约一半的患者经历了三级或更高级别的治疗相关不良事件。数据显示，6.4%的患者因不良事件而停止治疗，没有患者因分化综合征或QTc延长而停止治疗。。

This research is limited in that it was a single-arm study using historical standard of care as control to compare results with, rather than a randomized controlled trial. Several additional studies are ongoing to test the use of revumenib in combination with other standard-of-care acute leukemia treatments. .

这项研究的局限性在于它是一项单臂研究，使用历史护理标准作为对照来比较结果，而不是随机对照试验。另外几项研究正在进行中，以测试revumenib与其他标准治疗急性白血病联合使用的情况。。

The study was funded by Syndax, maker of revumenib.

这项研究由revumenib制造商Syndax资助。

Ibrahim Aldoss, MD, of City of Hope National Medical Center, will discuss this study in the Late-Breaking Abstracts Session on Tuesday, Dec. 12, 2023, at 9:00 a.m. Pacific time in Hall A (San Diego Convention Center).

希望之城国家医学中心医学博士易卜拉欣·奥尔德斯（IbrahimAldoss）将于2023年12月12日（星期二）上午9:00在太平洋时间a厅（圣地亚哥会议中心）的最新摘要会议上讨论这项研究。

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The American Society of Hematology (ASH) (hematology.org) is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 60 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology..

美国血液学会（ASH）（Hematology.org）是世界上最大的血液学家专业学会，致力于进一步了解，诊断，治疗和预防影响血液的疾病。60多年来，该协会通过促进血液学的研究，患者护理，教育，培训和宣传，领导了血液学作为一门学科的发展。。

ASH's flagship journal, Blood (bloodjournal.org) is the most cited peer-reviewed publication in the field, and Blood Advances (bloodadvances.org) is an open-access, online journal that publishes more peer-reviewed hematology research than any other academic journal worldwide. Two new journals will be joining the Blood Journals portfolio in 2024, Blood Neoplasia (bloodneoplasia.org) and Blood Vessels, Thrombosis & Hemostasis (bloodvth.org)..

ASH的旗舰期刊Blood（bloodjournal.org）是该领域被引用最多的同行评议出版物，Blood Advances（bloodadvances.org）是一种开放获取的在线期刊，其发表的同行评议血液学研究比全球任何其他学术期刊都要多。2024年，两种新期刊将加入血液期刊组合，即血液肿瘤（bloodneoplasia.org）和血管、血栓形成与止血（bloodvth.org）。。

SOURCE American Society of Hematology

来源：美国血液学会