Abstract：
BACKGROUND: Hypomethylating agents are approved in higher-riskmyelodysplastic syndromes. The combination of a hypomethylating agent with venetoclax is standard of care in acute myeloid leukaemia. We investigated the safety and activity of the first totally oral combination of decitabine plus cedazuridine and venetoclax in patients with higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia.
METHODS: We did a single-centre, dose-escalation and dose-expansion, phase 1/2, clinical trial. Patients with treatment-naive higher-risk-myelodysplastic syndromes or chronic myelomonocytic leukaemia (risk level categorised as intermediate-2 or higher by the International Prognostic Scoring System) with excess blasts (>5%). Treatment consisted of oral decitabine 35 mg plus cedazuridine 100 mg on days 1-5 and venetoclax (variable doses of 100-400 mg, day 1 to 14, 28-day cycle). The primary outcomes were safety for the phase 1 part and the overall response for the phase 2 part of the study. The trial is ongoing and this analysis was not prespecified. This study is registered with ClinicalTrials.gov, NCT04655755, and is currently enrolling participants.
RESULTS: Between Jan 21, 2021, and Jan 20, 2023, we enrolled 39 patients (nine in phase 1 and 30 in phase 2). The median age was 71 years (range 27-94), 28 (72%) patients were male, and 11 (28%) were female. The maximum tolerated dose was not reached, and the recommended phase 2 dose was established as oral decitabine 35 mg plus cedazuridine 100 mg for 5 days and venetoclax (400 mg) for 14 days. The most common grade 3-4 adverse events were thrombocytopenia (33 [85%] of 39), neutropenia (29 [74%]), and febrile neutropenia (eight [21%]). Four non-treatment-related deaths occurred on the study drugs due to sepsis (n=2), lung infection (n=1), and undetermined cause (n=1). The median follow-up time was 10·8 months (IQR 5·6-16·4). The overall response rate was 95% (95% CI 83-99; 37/39). 19 (49%) patients proceeded to hematopoietic stem-cell transplantation.
CONCLUSIONS: This early analysis suggests that the combination of oral decitabine plus cedazuridine with venetoclax for higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia is safe in most patients, with encouraging activity. Longer follow-up will be needed to confirm these data.
BACKGROUND: MD Anderson Cancer Center, MDS/AML Moon Shot, Genentech/AbbVie, and Astex Pharmaceuticals.
METHODS: We did a single-centre, dose-escalation and dose-expansion, phase 1/2, clinical trial. Patients with treatment-naive higher-risk-myelodysplastic syndromes or chronic myelomonocytic leukaemia (risk level categorised as intermediate-2 or higher by the International Prognostic Scoring System) with excess blasts (>5%). Treatment consisted of oral decitabine 35 mg plus cedazuridine 100 mg on days 1-5 and venetoclax (variable doses of 100-400 mg, day 1 to 14, 28-day cycle). The primary outcomes were safety for the phase 1 part and the overall response for the phase 2 part of the study. The trial is ongoing and this analysis was not prespecified. This study is registered with ClinicalTrials.gov, NCT04655755, and is currently enrolling participants.
RESULTS: Between Jan 21, 2021, and Jan 20, 2023, we enrolled 39 patients (nine in phase 1 and 30 in phase 2). The median age was 71 years (range 27-94), 28 (72%) patients were male, and 11 (28%) were female. The maximum tolerated dose was not reached, and the recommended phase 2 dose was established as oral decitabine 35 mg plus cedazuridine 100 mg for 5 days and venetoclax (400 mg) for 14 days. The most common grade 3-4 adverse events were thrombocytopenia (33 [85%] of 39), neutropenia (29 [74%]), and febrile neutropenia (eight [21%]). Four non-treatment-related deaths occurred on the study drugs due to sepsis (n=2), lung infection (n=1), and undetermined cause (n=1). The median follow-up time was 10·8 months (IQR 5·6-16·4). The overall response rate was 95% (95% CI 83-99; 37/39). 19 (49%) patients proceeded to hematopoietic stem-cell transplantation.
CONCLUSIONS: This early analysis suggests that the combination of oral decitabine plus cedazuridine with venetoclax for higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia is safe in most patients, with encouraging activity. Longer follow-up will be needed to confirm these data.
BACKGROUND: MD Anderson Cancer Center, MDS/AML Moon Shot, Genentech/AbbVie, and Astex Pharmaceuticals.
摘要：
背景：低甲基化药物被批准用于高危骨髓增生异常综合征。低甲基化剂与维奈托克的组合是急性髓性白血病的标准护理。我们调查了在高危骨髓增生异常综合征和慢性粒单核细胞白血病患者中首次完全口服地西他滨联合西达嗪和维奈托克的安全性和活性。
方法：我们做了一个单中心，剂量递增和剂量扩大，1/2期，临床试验。未经治疗的高风险骨髓增生异常综合征或慢性粒单核细胞白血病（国际预后评分系统分类为中等-2或更高的风险水平）患者，有过量的母细胞（>5％）。治疗包括在第1-5天口服地西他滨35mg加西他嗪100mg和维奈托克（可变剂量为100-400mg，第1天至14天，28天周期）。主要结果是研究1期部分的安全性和2期部分的总体反应。该试验正在进行中，该分析没有预先指定。这项研究在ClinicalTrials.gov注册，NCT04655755，目前正在招募参与者。
结果：在2021年1月21日至2023年1月20日之间，我们招募了39名患者（第一阶段9名，第二阶段30名）。中位年龄为71岁（范围27-94），28例（72%）患者为男性，11名(28%)为女性。未达到最大耐受剂量，推荐的2期剂量确定为口服地西他滨35mg加西达尿苷100mg，持续5天，韦内托克（400mg），持续14天。最常见的3-4级不良事件是血小板减少症（33[85%]39），中性粒细胞减少症（29[74%]），和发热性中性粒细胞减少症（8[21%]）。研究药物因败血症导致4例非治疗相关死亡（n=2），肺部感染（n=1），和未确定的原因（n=1）。中位随访时间为10·8个月(IQR5·6～16·4)。总有效率为95%（95%CI83-99；37/39）。19例（49％）患者进行了造血干细胞移植。
结论：这项早期分析表明，在大多数患者中，口服地西他滨联合西达嗪联合维奈托克治疗高危骨髓增生异常综合征和慢性粒单核细胞白血病是安全的，鼓励活动。需要更长时间的随访来确认这些数据。
背景：MD安德森癌症中心，MDS/AML月球射击，Genentech/AbbVie,和Astex制药公司。
方法：我们做了一个单中心，剂量递增和剂量扩大，1/2期，临床试验。未经治疗的高风险骨髓增生异常综合征或慢性粒单核细胞白血病（国际预后评分系统分类为中等-2或更高的风险水平）患者，有过量的母细胞（>5％）。治疗包括在第1-5天口服地西他滨35mg加西他嗪100mg和维奈托克（可变剂量为100-400mg，第1天至14天，28天周期）。主要结果是研究1期部分的安全性和2期部分的总体反应。该试验正在进行中，该分析没有预先指定。这项研究在ClinicalTrials.gov注册，NCT04655755，目前正在招募参与者。
结果：在2021年1月21日至2023年1月20日之间，我们招募了39名患者（第一阶段9名，第二阶段30名）。中位年龄为71岁（范围27-94），28例（72%）患者为男性，11名(28%)为女性。未达到最大耐受剂量，推荐的2期剂量确定为口服地西他滨35mg加西达尿苷100mg，持续5天，韦内托克（400mg），持续14天。最常见的3-4级不良事件是血小板减少症（33[85%]39），中性粒细胞减少症（29[74%]），和发热性中性粒细胞减少症（8[21%]）。研究药物因败血症导致4例非治疗相关死亡（n=2），肺部感染（n=1），和未确定的原因（n=1）。中位随访时间为10·8个月(IQR5·6～16·4)。总有效率为95%（95%CI83-99；37/39）。19例（49％）患者进行了造血干细胞移植。
结论：这项早期分析表明，在大多数患者中，口服地西他滨联合西达嗪联合维奈托克治疗高危骨髓增生异常综合征和慢性粒单核细胞白血病是安全的，鼓励活动。需要更长时间的随访来确认这些数据。
背景：MD安德森癌症中心，MDS/AML月球射击，Genentech/AbbVie,和Astex制药公司。
