Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
Blood Adv. 2022 Sep 27;6(18):5345-5355. doi: 10.1182/bloodadvances.2022007223.
We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR], 0.55; P < .001); both in younger (HR, 0.59; P < .001) and older patients (HR, 0.42; P < .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P < .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.
我们进行了一项单臂、2 期试验（德国-奥地利急性髓系白血病研究组[AMLSG]16-10），以评估米哚妥林联合强化化疗后进行异基因造血细胞移植（HCT）和 1 年米哚妥林维持治疗在伴有 fms 相关酪氨酸激酶 3（FLT3）内部串联重复（ITD）的成人急性髓系白血病（AML）患者中的疗效。符合条件的患者为年龄在 18 至 70 岁、新诊断为 FLT3-ITD 阳性 AML 的患者。主要和关键次要终点是无事件生存（EFS）和总生存（OS）。结果与 5 项 AMLSG 试验中 415 例既往治疗的患者的历史队列进行比较；采用双稳健调整的倾向评分加权和协变量调整进行统计学分析。结果还与癌症和白血病组 B（CALGB）10603/RATIFY 试验安慰剂组（18-59 岁）的患者进行了比较。该试验共入组 440 例患者（18-60 岁，n=312；61-70 岁，n=128）。多变量分析显示，与 AMLSG 16-10 试验的治疗患者相比，AMLSG 对照组的 EFS 显著有利（风险比[HR]，0.55；P<.001）；在年轻患者（HR，0.59；P<.001）和老年患者（HR，0.42；P<.001）中均如此。多变量分析还显示，与 AMLSG 对照组相比，OS 也有显著的获益（HR，0.57；P<.001），与 CALGB 10603/RATIFY 试验相比（HR，0.71；P=.005）。在包括异基因 HCT 作为时间依赖性协变量的敏感性分析中，米哚妥林的治疗效果仍然显著。在年轻和老年患者中，米哚妥林联合化疗是安全的。与历史对照相比，在强化治疗中加入米哚妥林可显著改善 AML 和 FLT3-ITD 患者的预后。该试验在 clinicaltrialsregistry.eu 上注册为 Eudra-CT 编号 2011-003168-63，并在 clinicaltrials.gov 上注册为 NCT01477606。
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