Chatzilygeroudi Theodora, Karantanos Theodoros, Pappa Vasiliki
Second Department of Internal Medicine and Research Unit, Hematology Unit, National and Kapodistrian University of Athens School of Medicine, Attikon University Hospital, 12462 Athens, Greece.
Division of Hematologic Malignancies and Bone Marrow Transplantation, Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cancers (Basel). 2025 May 7;17(9):1586. doi: 10.3390/cancers17091586.
Acute myeloid leukemia (AML) has traditionally been linked to a poor prognosis, particularly in older patients who are ineligible for intensive chemotherapy. The advent of Venetoclax, a powerful oral BH3 mimetic targeting anti-apoptotic protein BCL2, has significantly advanced AML treatment. Its combination with the hypomethylating agent azacitidine (AZA/VEN) has become a standard treatment for this group of AML patients, demonstrating a 65% overall response rate and a median overall survival of 14.7 months, compared to 22% and 8 months with azacitidine monotherapy, respectively. However, resistance and relapses remain common, representing a significant clinical challenge. Recent studies have identified molecular alterations, such as mutations in , , , and , as major drivers of resistance. Additionally, other factors, including metabolic changes, anti-apoptotic protein expression, and monocytic or erythroid/megakaryocytic differentiation status, contribute to treatment failure. Clinical trials are exploring strategies to overcome venetoclax resistance, including doublet or triplet therapies targeting IDH and FLT3 mutations; novel epigenetic approaches; menin, XPO1, and MDM2 inhibitors; along with immunotherapies like monoclonal antibodies and antibody-drug conjugates. A deeper understanding of the molecular mechanisms of resistance through single-cell analysis will be crucial for developing future therapeutic strategies.
急性髓系白血病（AML）传统上预后较差，尤其是对于不符合强化化疗条件的老年患者。维奈克拉（Venetoclax）的出现显著推动了AML治疗的进展，它是一种强效的口服BH3模拟物，可靶向抗凋亡蛋白BCL2。它与低甲基化药物阿扎胞苷联合使用（AZA/VEN）已成为这类AML患者的标准治疗方案，总体缓解率达65%，中位总生存期为14.7个月，而阿扎胞苷单药治疗的总体缓解率和中位总生存期分别为22%和8个月。然而，耐药和复发仍然很常见，这是一个重大的临床挑战。最近的研究已确定分子改变，如 、 、 和 中的突变，是耐药的主要驱动因素。此外，其他因素，包括代谢变化、抗凋亡蛋白表达以及单核细胞或红系/巨核细胞分化状态，也会导致治疗失败。临床试验正在探索克服维奈克拉耐药的策略，包括针对异柠檬酸脱氢酶（IDH）和FMS样酪氨酸激酶3（FLT3）突变的双联或三联疗法；新型表观遗传方法；Menin、染色体区域维护蛋白1（XPO1）和鼠双微体2（MDM2）抑制剂；以及单克隆抗体和抗体药物偶联物等免疫疗法。通过单细胞分析更深入地了解耐药的分子机制对于制定未来的治疗策略至关重要。
