DataSheet1_Clinical efficacy of azacytidine and venetoclax and prognostic impact of Tim-3 and galectin-9 in acute myeloid leukemia and high-risk myelodysplastic syndromes: A single-center real-life experience.docx

Treatment of acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) is difficult in older patients with comorbidities and high-risk disease factors. Venetoclax, the first-in-class Bcl-2 inhibitor, has proven efficacy and safety in combination with azacytidine for treatment of high-risk myeloid diseases. In this single-center real-life retrospective study, a total of 27 consecutive patients treated with azacytidine plus venetoclax were included, and clinical outcomes, hematological improvements, and biomarkers of responsiveness to therapy were compared to those observed in an historical cohort of 95 consecutive patients treated with azacytidine as single agent. Azacytidine plus venetoclax was effective and safe in older and frail AML and high-risk MDS patients, with median overall survival of 22.3 months, higher than that reported in phase III trial (14.7 months), and higher than that of historical cohort (5.94 months). Progression-free survival was higher in patients treated with the drug combination compared to those treated with azacytidine as single agent (p = 0.0065). Clinical benefits might increase when azacytidine and venetoclax are administered as upfront therapy (p = 0.0500). We showed that Tim-3 expression could be a promising therapeutic target in refractory/relapsed patients, and galectin-9 a biomarker of responsiveness to therapy. Moreover, patients treated with azacytidine and venetoclax displayed a higher overall survival regardless the presence of negative prognostic markers at diagnosis (e.g., increased WT1 copies and/or normalized blast count). These encouraging results in a real-world setting supported efficacy and safety of azacytidine plus venetoclax as upfront therapy in AML and high-risk MDS, with clinical outcomes comparable to those of clinical trials when an appropriate venetoclax management with bone marrow assessment at every first, second, fourth, and eighth cycle, and dose adjustments for toxicities are performed.

治疗老年合并多种疾病及高风险疾病因素的急性髓系白血病（AML）和高危骨髓增生异常综合征（MDS）颇具挑战。作为首类Bcl-2抑制剂，维奈克拉在与阿扎胞苷联合使用治疗高风险髓系疾病中已证实具有显著疗效和安全性。在本项单中心真实世界回顾性研究中，共纳入27例接受阿扎胞苷联合维奈克拉治疗的连续患者，并对其临床结果、血液学改善情况及对治疗的反应性生物标志物进行了比较，与既往95例仅接受阿扎胞苷治疗的连续患者历史队列进行比较。阿扎胞苷联合维奈克拉在老年且体质虚弱的AML和高危MDS患者中表现出有效性和安全性，其中位总生存期为22.3个月，高于III期临床试验报告的中位总生存期（14.7个月），也高于历史队列的中位总生存期（5.94个月）。与单药阿扎胞苷治疗相比，接受药物联合治疗的患者无进展生存期更高（p = 0.0065）。当阿扎胞苷和维奈克拉作为一线治疗方案时，临床获益可能增加（p = 0.0500）。本研究表明，Tim-3表达可能成为难治性/复发患者的潜在治疗靶点，而半乳糖凝集素-9则是治疗反应性的生物标志物。此外，无论在诊断时是否存在负面预后指标（例如，WT1拷贝数增加和/或未成熟细胞计数正常化），接受阿扎胞苷和维奈克拉治疗的患者均显示出更高的总生存率。这些在真实世界环境中获得的鼓舞人心的结果支持了阿扎胞苷联合维奈克拉作为一线治疗方案在AML和高危MDS治疗中的有效性和安全性，当进行适当的维奈克拉管理，包括在每个第一、第二、第四和第八周期进行骨髓评估，以及根据毒性进行剂量调整时，其临床结果可与临床试验相当。