Division of Hematology and Oncology, Department of Medicine, Seidman Cancer Center, Case Comprehensive Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH.
Department of Medicine, Section of Hematology/Oncology, West Virginia University Cancer Institute, Morgantown, WV.
Clin Lymphoma Myeloma Leuk. 2020 Apr;20(4):226-233.e1. doi: 10.1016/j.clml.2019.10.018. Epub 2019 Nov 6.
Midostaurin, a multikinase inhibitor, is approved for treatment of FLT3-mutant acute myeloid leukemia (AML). A phase I study established that midostaurin 75 mg orally twice daily for 14 days with standard dose azacitidine was safe and tolerable in elderly patients with AML. Herein, we report the phase II expansion cohort of previously untreated elderly or unfit patients with AML.
Primary objectives were to further describe the toxicity profile and determine the response rate in untreated patients with AML. Patients received midostaurin 75 mg orally twice daily on days 8 to 21 in combination with intravenous azacitidine at 75 mg/m on days 1 to 7. Plasma inhibitory activity assay for FLT3 was performed pretreatment and on day 8 and day 15 of each cycle.
Twenty-six patients (median age, 74 years; range, 59-85 years) with FLT3 wild-type AML were accrued. Patients received a median of 2 cycles of therapy (range, 1-10 cycles). Seven (29%) of 24 evaluable patients achieved a clinical response (4 complete response; 1 complete response with incomplete count recovery; and 2 partial response). The median overall survival was 244 days (95% confidence interval, 203-467 days). Hematologic, infectious, and gastrointestinal toxicities were comparable to similar studies. Peripheral blood FLT3 wild-type phosphorylation declined to 8% to 55% of pretreatment by day 15 of cycle 1 (7 patients) and declined with subsequent cycles (< 10% baseline) in 2 patients who were analyzed after cycle 3.
Multiple cycles of azacitidine and midostaurin were not well-tolerated, but persistent inhibition of FLT3 wild-type phosphorylation suggest intermittent dosing of midostaurin should be considered in future low-intensity regimens for FLT3-mutant AML.
多激酶抑制剂米哚妥林已获批用于治疗 FLT3 突变型急性髓系白血病（AML）。一项 I 期研究表明，米哚妥林 75mg 每日口服 2 次，连用 14 天，与标准剂量阿扎胞苷联合应用，在老年 AML 患者中是安全且耐受良好的。在此，我们报告了未经治疗的老年或不适合治疗的 AML 患者的 II 期扩展队列研究结果。
主要目的是进一步描述未治疗 AML 患者的毒性谱，并确定缓解率。患者接受米哚妥林 75mg 每日口服 2 次，连用 14 天，在第 8 天至 21 天，同时静脉给予阿扎胞苷 75mg/m2，在第 1 天至第 7 天。在每个周期的第 8 天和第 15 天进行 FLT3 血浆抑制活性检测。
共入组 26 例 FLT3 野生型 AML 患者（中位年龄 74 岁，范围 59-85 岁）。患者接受了中位数为 2 个周期的治疗（范围 1-10 个周期）。24 例可评估患者中 7 例（29%）获得了临床缓解（4 例完全缓解，1 例完全缓解伴不完全血细胞计数恢复，2 例部分缓解）。中位总生存期为 244 天（95%置信区间为 203-467 天）。血液学、感染和胃肠道毒性与类似研究相似。外周血 FLT3 野生型磷酸化在第 1 个周期的第 15 天降至 8%-55%（7 例患者），并在随后的周期中下降（2 例患者在第 3 个周期后分析，降至<10%基线）。
阿扎胞苷和米哚妥林的多个周期治疗不能耐受良好，但持续抑制 FLT3 野生型磷酸化表明，在未来针对 FLT3 突变型 AML 的低强度治疗方案中，应考虑间歇性给予米哚妥林。
