Hypomethylating agents combined with venetoclax are effective regimens in patients with acute myeloid leukaemia who are ineligible for intensive chemotherapy. Decitabine and cedazuridine (ASTX727) is an oral formulation of decitabine that achieves equivalent area-under-curve exposure to intravenous decitabine. We performed a single centre phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax. This study enrolled patients with newly diagnosed (frontline treatment group) acute myeloid leukaemia who were ineligible for intensive chemotherapy (aged ≥75 years, an Eastern Cooperative Oncology Group [ECOG] performance status of 2–3, or major comorbidities) or relapsed or refractory acute myeloid leukaemia. Being aged 18 years or older and having an ECOG performance status of 2 or less were requirements for the relapsed or refractory disease treatment cohort, without any limits in the number of previous lines of therapy. Treatment consisted of ASTX727 (cedazuridine 100 mg and decitabine 35 mg) orally for 5 days and venetoclax 400 mg orally for 21–28 days in 28-day cycles. The primary outcome was overall response rate of ASTX727 plus venetoclax. Living patients who have not completed cycle one were not evaluable for response. Safety was analysed in all patients who started treatment. This study was registered on () and is ongoing. The data cutoff date for this analysis was Sept 22, 2023. Between March 16, 2021, and Sept 18, 2023, 62 patients were enrolled (49 frontline and 13 relapsed or refractory) with a median age of 78 years (IQR 73–82). 36 (58%) were male; 53 (85%) were White, 4 (6%) Black, 2 (3%) Asian and 3 (5%) other or did not answer. 48 (77%) of 62 patients were European LeukemiaNet 2022 adverse risk, 24 (39%) had antecedent myelodysplastic syndromes, 12 (19%) had previously failed a hypomethylating agent, ten (16%) had therapy-related acute myeloid leukaemia, and 11 (18%) had mutations. The median follow-up time was 18·3 months (IQR 8·8–23·3). The overall response rate was 30 (64%) of 47 patients (95% CI 49–77) in frontline cohort and six (46%) of 13 patients (19–75) in relapsed or refractory cohort. The most common grade 3 or worse treatment-emergent adverse events were febrile neutropenia in 11 (18%) of 62 patients, pneumonia in eight (13%), respiratory failure in five (8%), bacteraemia in four (6%), and sepsis in four (6%). Three deaths occurred in patients in remission (one sepsis, one gastrointestinal haemorrhage, and one respiratory failure) and were potentially treatment related. ASTX727 plus venetoclax is an active fully oral regimen and safe in most older or unfit patients with acute myeloid leukaemia. Our findings should be confirmed in larger multicentric studies. MD Anderson Cancer Center Support Grant, Myelodysplastic Syndrome/Acute Myeloid Leukaemia Moon Shot, Leukemia SPORE, Taiho Oncology, and Astex Pharmaceuticals.

中文翻译：

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口服地西他滨和西达他啶加维奈托克治疗老年或身体不适的急性髓系白血病患者：一项 2 期研究

对于不适合强化化疗的急性髓系白血病患者，低甲基化药物联合维奈托克是有效的治疗方案。地西他滨和西达嗪 (ASTX727) 是地西他滨的口服制剂，可达到与静脉注射地西他滨相同的曲线下面积暴露量。我们进行了一项单中心 2 期研究来评估 ASTX727 联合 Venetoclax 的疗效和安全性。本研究纳入了新诊断的（一线治疗组）急性髓性白血病患者，这些患者不适合强化化疗（年龄≥75岁，东部肿瘤合作组[ECOG]表现状态为2-3，或有主要合并症）或复发或难治性患者急性粒细胞白血病。复发或难治性疾病治疗队列的要求是年龄在 18 岁或以上且 ECOG 体能状态为 2 或更低，且先前治疗的次数没有任何限制。治疗包括口服ASTX727（西达嗪100毫克和地西他滨35毫克）5天，以及口服维奈托克400毫克21-28天，周期为28天。主要结局是 ASTX727 加维奈托克的总体缓解率。未完成第一周期的活着的患者无法评估反应。对所有开始治疗的患者进行安全性分析。这项研究已在 () 上注册并正在进行中。本次分析的数据截止日期为 2023 年 9 月 22 日。2021 年 3 月 16 日至 2023 年 9 月 18 日期间，纳入了 62 名患者（49 名一线患者和 13 名复发或难治性患者），中位年龄为 78 岁（IQR 73-82） ）。 36 名（58%）为男性； 53 名 (85%) 是白人，4 名 (6%) 是黑人，2 名 (3%) 是亚洲人，3 名 (5%) 是其他人或没有回答。 62 名患者中有 48 名 (77%) 属于欧洲白血病网 2022 年不良风险，24 名 (39%) 患有既往骨髓增生异常综合征，12 名 (19%) 之前使用过低甲基化药物失败，10 名 (16%) 患有治疗相关的急性髓系白血病， 11 人（18%）有突变。中位随访时间为 18·3 个月 (IQR 8·8–23·3)。一线队列中 47 名患者 (95% CI 49-77) 中的总体缓解率为 30 例 (64%)，复发或难治性队列中 13 名患者 (19-75) 中总体缓解率为 6 例 (46%)。最常见的 3 级或更严重的治疗引起的不良事件是 62 名患者中的 11 名患者（18%）出现发热性中性粒细胞减少症，8 名患者（13%）出现肺炎，5 名患者（8%）出现呼吸衰竭，4 名患者（6%）出现菌血症，四人（6%）患有败血症。缓解期患者中有 3 例死亡（1 例脓毒症、1 例胃肠道出血和 1 例呼吸衰竭），并且可能与治疗有关。 ASTX727 加维奈托克是一种积极的完全口服疗法，对于大多数老年或身体不适的急性髓系白血病患者来说是安全的。我们的研究结果应该在更大规模的多中心研究中得到证实。 MD 安德森癌症中心支持拨款、骨髓增生异常综合征/急性髓系白血病 Moon Shot、白血病 SPORE、Taiho Oncology 和 Astex Pharmaceuticals。