Gilteritinib为基础的方案桥接异基因造血干细胞移植对复发难治伴FLT3-ITD突变急性髓系白血病患者的疗效及安全性研究

Efficacy and safety of gilteritinib-based combination therapy bridging allo-HSCT in relapsed or refractory acute myeloid leukemia patients with positive FLT3-ITD mutation

目的探讨Gilteritinib(Gilt)为基础的方案桥接异基因造血干细胞移植(allo-HSCT)对伴FMS样酪氨酸激酶3(FLT3)基因内部串联重复(ITD)突变的复发难治性急性髓系白血病(R/R AML)患者的安全性、有效性,以及移植后Gilt维持治疗对FLT3-ITD阳性R/R AML患者预后的影响。方法回顾性分析2019年8月至2023年1月苏州大学附属第一医院收治的26例伴FLT3-ITD突变的R/R AML患者。统计所有纳入患者的复合完全缓解(CRc)率、总生存(OS)期、无病生存(DFS)期和不良反应。结果26例FLT3-ITD突变阳性R/R AML患者中,男14例,女12例,中位年龄38(18~65)岁。难治18例,复发8例。用药第14~21天疗效:完全缓解(CR)率为26.9%(7/26),CR伴血液学不完全恢复(CRi)率为57.7%(15/26),部分缓解(PR)率为7.7%(2/26),CRc率为84.6%(22/26),微小残留病(MRD)转阴率为65.4%。所有患者12、24个月累计OS率分别为79.0%和72.0%。中位OS期未达到。中位随访时间为16.0个月。全部治疗有效患者12、24个月累计DFS率分别为78.0%和71.0%。中位DFS期未达到。接受allo-HSCT的患者中位OS期未达到,较未接受allo-HSCT的患者(3.3个月,95%CI 2.2~4.3个月)显著延长(P=0.005)。移植后是否应用Gilt维持治疗的患者中位OS期均未达到,且移植后维持治疗的患者OS明显优于移植后未进行维持治疗的患者(P=0.019)。本研究中FLT3-ITD基因突变清除率为38.5%,且FLT3-ITD基因突变转阴的患者中位OS期未达到,明显长于未转阴的患者(15.0个月)(P=0.018)。Gilt为基础的方案最常见的3级及以上血液学不良反应包括白细胞减少(76.9%)、中性粒细胞减少(76.9%)、中性粒细胞减少性发热(61.5%)、血小板减少(69.2%)和贫血(57.7%)。其中1例患者在移植后口服Gilt维持治疗时出现分化综合征,治疗后好转。结论Gilt为基础的方案桥接allo-HSCT治疗FLT3-ITD突变阳性R/R AML患者的CRc率较高,MRD转阴率也较高,起效迅速,有效延长患者生存期。此外,FLT3-ITD基因突变清除率较高,且桥接移植和移植后Gilt维持治疗明显改善患者生存。治疗过程中不良事件的监测和管理至关重要。

Objective This study aims to evaluate the safety and effectiveness of gilteritinib(Gilt)-based combination therapy bridging allo-HSCT for FLT3-ITD+R/R AML.Additionally,it aims to assess the impact of Gilt maintenance therapy on the prognosis of patients after allo-HSCT.Methods The clinical data of 26 patients with FLT3-ITD+R/R AML treated at the First Affiliated Hospital of Soochow University from August 2019 to January 2023 were retrospectively analyzed.The analysis included an assessment of the composite complete remission rate(CRc),overall survival(OS)time,disease-free survival(DFS)time,and adverse events experienced by all enrolled patients.Results A total of 26 patients with FLT3-ITD+R/R AML were enrolled,including 14 men and 12 women with a median age of 38(18-65)years.A total of 18 cases were refractory,and eight cases were relapsed.The curative effect evaluation conducted between 14 and 21 days showed that the complete remission(CR)rate was 26.9%(7/26),the CR with hematology incomplete recovery was 57.7%(15/26),and the partial response(PR)rate was 7.7%(2/26).The CRc was 84.6%(22/26),and the minimal residual disease(MRD)negativity rate was 65.4%.The 12 month cumulative OS rate for all patients was 79.0%,and the 24 month cumulative OS rate was 72.0%.The median OS time was not determined.The median follow-up time was 16.0 months.Among the patients who responded to treatment,the 12 month cumulative DFS rate was 78.0%,and the 24 month cumulative DFS rate was 71.0%.The median DFS time was not determined.Patients who received allo-HSCT had a median OS time that was significantly longer than those who did not receive allo-HSCT(3.3 months,95%CI 2.2-4.3 months,P=0.005).The median OS time of patients with or without Gilt maintenance therapy after allo-HSCT was not determined,but the OS time of patients with Gilt maintenance therapy after allo-HSCT treatment was longer than that of patients without Gilt maintenance therapy after allo-HSCT treatment(P=0.019).The FLT3-ITD mutation clearance rate in this study was 38.5%,and the median OS time of patients with FLT3-ITD mutation clearance was not determined but was significantly longer than the median OS of patients without FLT3-ITD mutation clearance(15.0 months;P=0.018).The most common grade 3 and above hematological adverse events of Gilt-based combination therapy included leukopenia(76.9%),neutropenia(76.9%),febrile neutropenia(61.5%),thrombocytopenia(69.2%),and anemia(57.7%).One patient developed differentiation syndrome during oral Gilt maintenance therapy after allo-HSCT treatment,but his condition improved after treatment.Conclusion The Gilt-based combination therapy is highly effective in treating FLT3-ITD+R/R AML.It demonstrates a high CRc,MRD negativity rate,and rapid onset,leading to a significant improvement in patients'survival.Furthermore,the clearance rate of FLT3-ITD mutation is notably high.Additionally,implementing bridging allo-HSCT and Gilt maintenance therapy after allo-HSCT treatment has considerably enhances patients'survival.Closely monitoring and managing any adverse event that may occur during treatment are crucial.