Alisertib plus induction chemotherapy in previously untreated patients with high-risk, acute myeloid leukaemia: a single-arm, phase 2 trial.
Alisertib plus induction chemotherapy in previously untreated patients with high-risk, acute myeloid leukaemia: a single-arm, phase 2 trial.
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DOI：
10.1016/s2352-3026(19)30203-0
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发表时间：
2020-02
期刊：
影响因子：
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通讯作者：
Fathi AT
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作者：
Brunner AM;Blonquist TM;DeAngelo DJ;McMasters M;Fell G;Hermance NM;Winer ES;Lindsley RC;Hobbs GS;Amrein PC;Hock HR;Steensma DP;Garcia JS;Luskin MR;Stone RM;Ballen KK;Rosenblatt J;Avigan D;Nahas MR;Mendez LM;McAfee SL;Moran JA;Bergeron M;Foster J;Bertoli C;Manning AL;McGregor KL;Fishman KM;Kuo FC;Baltay MT;Macrae M;Burke M;Behnan T;Wey MC;Som TT;Ramos AY;Rae J;Lombardi Story J;Nelson N;Logan E;Connolly C;Neuberg DS;Chen YB;Graubert TA;Fathi AT
急性髓系白血病(AML)患者存在AAK蛋白表达增高，抑制AAK基因表达有望成为治疗AML的新靶点。这项II期研究的目的是评估这种联合治疗高危急性髓细胞白血病的活性。这项第二阶段试验是在马萨诸塞州波士顿的达纳-法伯/哈佛癌症中心进行的。我们包括未经治疗的成人急性髓细胞白血病患者，ECOG 0-2，存在不良风险核型，继发性急性髓细胞白血病，与治疗相关的急性髓细胞白血病，和/或年龄≥65岁。阿糖胞苷100 mg/m2/d，第1~7天，伊达比星12 mg/m2/d，第1~3天。阿司替布30 mg，口服，每日2次，第8~15天。阿糖胞苷和阿司替布最多可接受4个巩固周期，维持12个月。主要终点为综合完全缓解率(CR+CRI)。我们使用了Simon的两阶段设计，假设零CR+CRI为45%。分析是按方案进行的。该试验已注册(Clinicaltrials.gov，NCT02560025)，并已完成招募。我们在2015年12月31日至2017年8月1日期间招募了39名符合条件的患者；中位随访时间为13.7个月(IQR 12.7-14.4)。19例(49%)为继发性AML，3例为治疗相关AML。中期诱导时，33例(85%)表现为骨髓再生障碍，6例(15%)再次诱导。30d和60d的死亡率分别为8%和13%。综合缓解率%，CR20例(51%)，CR5例(13%)。有1例PR，8例(21%)难治，5例(13%)在疗效评估前死亡，无治疗相关死亡。最常见的3级或4级不良反应包括发热性中性粒细胞减少14例，中性粒细胞减少12例，血小板减少12例，贫血11例，厌食9例，口腔粘膜炎4例。阿利瑟布联合诱导化疗在这一不利的白血病亚群中显示出%的缓解率。这项研究符合未来对以前未治疗的高危急性髓细胞白血病进行随机试验的标准。
Increased aurora A kinase (AAK) expression occurs in acute myeloid leukemia (AML); AAK inhibition is a promising therapeutic target in this disease. The aim of this phase II study was to assess activity of this combination in high-risk AML. This Phase II trial was conducted at Dana-Farber/Harvard Cancer Center in Boston, MA. We included untreated adult AML patients, ECOG 0–2, harboring an adverse-risk karyotype, secondary AML, therapy-related AML, and/or age ≥65 years. Patients received continuous infusion cytarabine 100mg/m2/day days 1–7 and idarubicin 12mg/m2/day days 1–3. Alisertib 30mg was administered orally twice daily days 8–15. Patients could receive up to 4 consolidation cycles with cytarabine and alisertib, and alisertib maintenance for 12 months. The primary endpoint was the rate of composite complete remission (CR+CRi). We used a Simon two-stage design, assuming a null CR+CRi of 45%. Analyses were per-protocol. The trial is registered (clinicaltrials.gov, NCT02560025) and has completed enrollment. We enrolled 39 eligible patients between December 31, 2015 and August 1, 2017; median follow up was 13.7mo (IQR 12.7–14.4). 19 patients (49%) had secondary AML and 3 had therapy-related AML. At mid-induction, 33 (85%) demonstrated marrow aplasia, 6 (15%) received re-induction. Mortality at 30 and 60 days was 8% and 13%, respectively. The composite remission rate was 64%: 20 (51%) CR and 5 (13%) CRi. There was 1 PR, 8 (21%) were refractory, and 5 (13%) died before response assessment, with no treatment-related deaths. The most common grade 3 or 4 adverse events included febrile neutropenia (n=14), neutropenia (n=12), thrombocytopenia (n=12), anemia (n=11), anorexia (n=9), and oral mucositis (n=4). Alisertib combined with induction chemotherapy demonstrated a rate of remission of 64% in this unfavorable leukemia subset. This study met criteria to move forward to a future randomized trial in previously untreated high-risk AML.