10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial.
10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial.
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DOI：
10.1016/s2352-3026(20)30210-6
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Konopleva MY
中科院分区：
文献类型：
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作者：
DiNardo CD;Maiti A;Rausch CR;Pemmaraju N;Naqvi K;Daver NG;Kadia TM;Borthakur G;Ohanian M;Alvarado Y;Issa GC;Montalban-Bravo G;Short NJ;Yilmaz M;Bose P;Jabbour EJ;Takahashi K;Burger JA;Garcia-Manero G;Jain N;Kornblau SM;Thompson PA;Estrov Z;Masarova L;Sasaki K;Verstovsek S;Ferrajoli A;Weirda WG;Wang SA;Konoplev S;Chen Z;Pierce SA;Ning J;Qiao W;Ravandi F;Andreeff M;Welch JS;Kantarjian HM;Konopleva MY
静脉滴注去甲基化药物是新诊断的75岁以上或不适合强化化疗的急性髓系白血病(AML)患者的一种新的治疗标准。药效学研究表明，较长的10天地西他滨方案的优越性，该方案在高危AML的2期试验中显示出有希望的结果。我们推测维尼替克联合10天地西他滨治疗ND和复发/难治性(R/R)AML可能有效，特别是对高危亚组。这项II期研究纳入了168名年龄超过60岁的ND AML、继发性AML(SAML)和R/R AML患者。患者脑电地形图评分3分及以下，白细胞<10×109/L，终末器官功能良好。根据治疗医生的评估，不符合强化化疗的条件。具有有利风险细胞遗传学的患者，例如t(15；17)或核心结合因子AML，或既往接受bcl2抑制剂治疗的患者被排除在外。静脉滴注地西他滨20 mg/m~2，10天后口服维尼替克400 mg/d(DEC10-VEN)诱导，然后用地西他滨5天联合维尼替克巩固。主要疗效终点为总有效率(ORR)。这项试验在ClinicalTrials.gov上注册，编号为NCT03404193，并继续吸引患者。在2018年1月19日至2019年12月16日期间，我们招募了70名患者；(42%)患有ND AML，15名患者(9%)患有未经治疗的SAML，28名患者(17%)接受过治疗，55名患者(33%)患有R/R AML。中位年龄为71岁(IQR，65-76)，30%的患者ECOG功能状态为2或更高。所有患者的ORR为74%(95%CI 67，80)，疾病亚组为ND AML，89%(95%CI 79，94)；初治SAML，80%(95%CI 55，93)；治疗SAML，61%(95%CI 42，76)；R/R AML，62%(95%CI 49，74)。最常见的紧急不良反应包括感染合并3/4级中性粒细胞减少症(n=84，50%)和发热中性粒细胞减少症(n=49，29%)。共有6例5级不良事件，其中5例感染与治疗相关的3/4级中性粒细胞减少，1例肾功能衰竭与研究方案无关。DEC10-VEN是安全的，在ND AML和分子定义的R/R AML亚群中具有高活性。NIH/NCI R01CA235622
Venetoclax with hypomethylating agents is a new standard of care for newly diagnosed (ND) patients with acute myeloid leukemia (AML) who are 75 years or older, or unfit for intensive chemotherapy. Pharmacodynamic studies have suggested superiority of the longer 10-day regimen of decitabine which has shown promising results in high-risk AML in phase 2 trials. We hypothesized that venetoclax with 10-day decitabine may be effective in ND and relapsed/refractory (R/R) AML, particularly for high-risk subgroups. This phase II study enrolled 168 patients with ND AML older than 60 years, secondary AML (sAML), and R/R AML. Patients were required to have an ECOG performance status of 3 or less, WBC less than 10×109/L, and adequate end-organ function. Ineligibility for intensive chemotherapy was based on the treating physicians’ assessment. Patients with favorable-risk cytogenetics, e.g., t(15;17) or core-binding factor AML, or prior BCL2-inhibitor therapy were excluded. Patients received decitabine 20mg/m2 IV for 10-days with oral venetoclax 400mg daily (DEC10-VEN) for induction, followed by decitabine 5-days with venetoclax for consolidation. The primary efficacy endpoint was overall response rate (ORR). The trial was registered on Clinicaltrials.gov, number NCT03404193 and continues to accrue patients. Between January 19, 2018 and December 16, 2019, we enrolled 70 patients; (42%) had ND AML, 15 patients (9%) had untreated sAML, 28 patients (17%) had treated sAML, and 55 patients (33%) had R/R AML. The median age was 71 years (IQR, 65–76) and 30% patients had ECOG performance status of 2 or higher. The ORR among all patients was 74% (95% CI 67, 80) and in disease subgroups were: ND AML, 89% (95% CI 79, 94); untreated sAML, 80% (95% CI 55, 93); treated sAML, 61% (95% CI 42, 76); and R/R AML, 62% (95% CI 49, 74). The most common treatment-emergent adverse events included infections with grade 3/4 neutropenia (n=84, 50%) and febrile neutropenia (n=49, 29%). There were six grade 5 adverse events including five infections with therapy-related grade 3/4 neutropenia, and one case of renal failure unrelated to study regimen. DEC10-VEN is safe and has high activity in ND AML and molecularly defined R/R AML subsets. NIH/NCI R01CA235622