Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lancet Haematol. 2022 May;9(5):e350-e360. doi: 10.1016/S2352-3026(22)00076-X.
Venetoclax combined with intensive chemotherapy has been shown to be safe with promising activity in fit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to compare the activity of venetoclax plus intensive chemotherapy with intensive chemotherapy alone.
This was a post-hoc propensity score matched analysis of prospective clinical trials (NCT03214562, NCT02115295, and NCT01289457) in patients at The University of Texas MD Anderson Cancer Center, Texas, USA between March 29, 2010, and June 15, 2021. Eligible patients were aged 18 years and older, and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and were treated within trials incorporating purine analogues with an anthracycline and cytarabine either with venetoclax plus intensive chemotherapy or with intensive chemotherapy alone. Patients in the venetoclax plus intensive chemotherapy cohort were matched with patients in the intensive chemotherapy cohort. Morphological response and measurable residual disease (MRD) was assessed using bone marrow aspiration and biopsy and eight-colour multiparameter flow cytometry. The primary objectives were rate of MRD negative composite complete response and cumulative incidence of transition to allogeneic haematopoietic stem-cell transplantation (HSCT). All patients who had response within two treatment cycles (induction and re-induction) were included in the analyses. Secondary objectives included assessment of event-free and overall survival.
The propensity matched cohort included 279 patients (median age 49 years [IQR 39-57]; 131 [47%] were men and 148 [53%] were women); 85 in the venetoclax plus intensive chemotherapy cohort and 194 in the intensive chemotherapy cohort. After a median follow up of 30 months (95% CI 26-36), 64 (86%) of 74 patients in the venetoclax plus intensive chemotherapy cohort had an MRD-negative composite complete response rate compared with 86 [61%] of 140 patients in the intensive chemotherapy cohort (odd ratio 3·2 [95% CI 1·5-6·7]; p=0·0028). The overall cumulative incidence of allogeneic HSCT in responding patients was higher with venetoclax plus intensive chemotherapy than intensive chemotherapy (79% [95% CI 67-88] vs 57% [49-65]; hazard ratio [HR] 1·52 [95% CI 1·11-2·08]; p=0·012). Venetoclax plus intensive chemotherapy improved event-free survival (median not reached [NR; 95% CI NR-NR] vs 14·3 months [10·7-33·5]; HR 0·57 [95% CI 0·34-0·95]; p=0·030), but overall survival did not significantly differ between the two cohorts (median NR [95% CI 24-NR] vs 32 months [19-NR]; HR 0·63 [95% CI 0·35-1·1], p=0·13).
Venetoclax combined with intensive induction chemotherapy induced deep MRD-negative remissions, allowing transition to allogeneic HSCT in first remission, and improvement in event-free survival. These results highlight the incremental benefit of venetoclax added to intensive induction chemotherapy across European LeukemiaNet risk groups, and serve as a benchmark to inform enrolment on future confirmatory prospective clinical trials.
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在适合的新诊断急性髓系白血病患者中，维奈托克联合强化化疗显示出安全性和有希望的活性。本研究的目的是比较维奈托克联合强化化疗与强化化疗的疗效。
这是在美国德克萨斯州 MD 安德森癌症中心进行的两项前瞻性临床试验（NCT03214562、NCT02115295 和 NCT01289457）的事后倾向评分匹配分析，纳入标准为年龄在 18 岁及以上、新诊断为急性髓系白血病或高危骨髓增生异常综合征，且在纳入嘌呤类似物联合蒽环类和阿糖胞苷的试验中接受治疗，包括维奈托克联合强化化疗或强化化疗。维奈托克联合强化化疗组的患者与强化化疗组的患者进行匹配。采用骨髓穿刺和活检以及八色多参数流式细胞术评估形态学反应和可测量残留疾病（MRD）。主要目的是评估 MRD 阴性复合完全缓解率和异基因造血干细胞移植（HSCT）的累积发生率。所有在两个治疗周期（诱导和再诱导）内有反应的患者均纳入分析。次要目的包括评估无事件生存和总生存。
在倾向评分匹配的队列中纳入了 279 例患者（中位年龄 49 岁[IQR 39-57]；131 例[47%]为男性，148 例[53%]为女性）；维奈托克联合强化化疗组 85 例，强化化疗组 194 例。中位随访 30 个月（95%CI 26-36）后，维奈托克联合强化化疗组 74 例患者中有 64 例（86%）达到 MRD 阴性复合完全缓解率，而强化化疗组 140 例患者中有 86 例（61%）（比值比 3.2[95%CI 1.5-6.7]；p=0.0028）。有反应的患者接受维奈托克联合强化化疗的异基因 HSCT 的总累积发生率高于强化化疗（79%[95%CI 67-88]vs 57%[49-65]；风险比[HR]1.52[95%CI 1.11-2.08]；p=0.012）。维奈托克联合强化化疗改善了无事件生存（未达到中位无事件生存[NR；95%CI NR-NR]vs 14.3 个月[10.7-33.5]；HR 0.57[95%CI 0.34-0.95]；p=0.030），但两组的总生存无显著差异（NR 中位无事件生存[95%CI 24-NR]vs 32 个月[19-NR]；HR 0.63[95%CI 0.35-1.1]；p=0.13）。
维奈托克联合强化诱导化疗可诱导深度 MRD 阴性缓解，允许在首次缓解期进行异基因 HSCT，并改善无事件生存。这些结果突出了维奈托克在欧洲白血病网风险组中联合强化诱导化疗的附加获益，并为未来的前瞻性临床试验提供了登记的基准。
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