Department of Hematology, Hospital de la Santa Creu i Sant Pau, Sant Pau Biomedical Research Institute. Universitat Autonoma of Barcelona, Barcelona, Spain.
Hospital Universitari i Politècnic La Fe, Valencia, Spain.
Blood Adv. 2023 Nov 14;7(21):6441-6450. doi: 10.1182/bloodadvances.2023009847.
The pivotal RATIFY study demonstrated midostaurin (50 mg twice daily) with standard chemotherapy significantly reduced mortality in adult patients (<60 years) with newly diagnosed (ND) FLT3mut acute myeloid leukemia (AML). Considering that AML often present in older patients who show poor response to chemotherapy, this open-label, multicenter phase 3b trial was designed to further assess safety and efficacy of midostaurin plus chemotherapy in induction, consolidation, and maintenance monotherapy in young (≤60 years) and older (>60 years) patients with FLT3mut ND-AML. Compared with RATIFY, this study extended midostaurin treatment from 14 days to 21 days, substituted anthracyclines (idarubicin or daunorubicin), and introduced variation in standard combination chemotherapy dosing ("7+3" or "5+2" in more fragile patients). Total 301 patients (47.2% >60 years and 82.7% with FLT3-ITDmut) of median age 59 years entered induction phase. Overall, 295 patients (98.0%) had at least 1 adverse event (AE), including 254 patients (84.4%) with grade ≥3 AE. The grade ≥3 serious AEs occurred in 134 patients. No difference was seen in AE frequency between age groups, but grade ≥3AE frequency was higher in older patients. Overall, complete remission (CR) rate including incomplete hematologic recovery (CR + CRi) (80.7% [95% confidence interval, 75.74-84.98]) was comparable between age groups (≤60 years [83.5%]; >60 to ≤70 years [82.5%]; in patients >70 years [64.1%]) and the type of anthracycline used in induction. CR + CRi rate was lower in males (76.4%) than females (84.4%). Overall, the safety and efficacy of midostaurin remains consistent with previous findings, regardless of age, sex, or induction regimen. The trial is registered at www.clinicaltrials.gov as #NCT03379727.
关键性 RATIFY 研究表明，米哚妥林（每日两次，50mg）联合标准化疗可显著降低新诊断（ND）FLT3 突变急性髓系白血病（AML）成人患者的死亡率。鉴于 AML 通常发生在对化疗反应不佳的老年患者中，因此，这项开放标签、多中心 3b 期试验旨在进一步评估米哚妥林联合化疗在诱导、巩固和维持治疗年轻（≤60 岁）和老年（>60 岁）FLT3 突变 ND-AML 患者中的安全性和疗效。与 RATIFY 相比，本研究将米哚妥林的治疗时间从 14 天延长至 21 天，用蒽环类药物（伊达比星或柔红霉素）替代，并对标准联合化疗剂量进行了调整（脆弱患者采用“7+3”或“5+2”方案）。中位年龄为 59 岁的 301 名患者（47.2%>60 岁，82.7%FLT3-ITDmut）入组诱导期。总体而言，295 名患者（98.0%）至少出现 1 次不良事件（AE），包括 254 名患者（84.4%）出现≥3 级 AE。134 名患者发生≥3 级严重 AE。两组间 AE 发生率无差异，但老年患者≥3 级 AE 发生率更高。总体而言，完全缓解（CR）率（包括不完全血液学恢复的 CR+CRi）（80.7%[95%置信区间，75.74-84.98]）在两组间相似（≤60 岁组[83.5%]；>60 至≤70 岁组[82.5%]；>70 岁组[64.1%]），且诱导方案中蒽环类药物的类型也相似。CR+CRi 率在男性（76.4%）中低于女性（84.4%）。总体而言，米哚妥林的安全性和疗效与既往研究结果一致，与年龄、性别或诱导方案无关。该试验在 www.clinicaltrials.gov 上注册，编号为 #NCT03379727。
