索拉非尼联合标准化疗治疗高等位基因比/ITD+急性髓系白血病患儿：来自儿童肿瘤学组协议 AAML1031 的报告。
Sorafenib in Combination With Standard Chemotherapy for Children With High Allelic Ratio /ITD+ Acute Myeloid Leukemia: A Report From the Children's Oncology Group Protocol AAML1031.
机构信息
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
Harvard Medical School, Boston, MA.
出版信息
J Clin Oncol. 2022 Jun 20;40(18):2023-2035. doi: 10.1200/JCO.21.01612. Epub 2022 Mar 29.
PURPOSE
High allelic ratio (HAR) /ITD (AR > 0.4) mutations confer poor prognosis in pediatric acute myeloid leukemia (AML). COG AAML1031 studied the feasibility and efficacy of adding sorafenib, a multikinase tyrosine kinase inhibitor to standard chemotherapy and as single-agent maintenance therapy in this population.
MATERIALS AND METHODS
Patients were treated in three cohorts. The initial safety phase defined the maximum tolerated dose of sorafenib starting in induction 2. Cohorts 2 and 3 added sorafenib in induction and as single-agent maintenance. Clinical outcome analysis was limited to n = 72 patients in cohorts 2/3 and compared with n = 76 HAR /ITD+ AML patients who received identical chemotherapy without sorafenib. Sorafenib pharmacokinetics and plasma inhibitory activity were measured in a subset of patients.
RESULTS
The maximum tolerated dose of sorafenib was 200 mg/m once daily; dose-limiting toxicities included rash (n = 2; 1 grade 3 and 1 grade 2), grade 2 hand-foot syndrome, and grade 3 fever. Pharmacokinetics/plasma inhibitory activity data demonstrated that measured plasma concentrations were sufficient to inhibit phosphorylated FLT3. Although outcomes were superior with sorafenib in cohorts 2 and 3, patients treated with sorafenib also underwent hematopoietic stem-cell transplant more frequently than the comparator population. Multivariable analysis that accounted for both hematopoietic stem-cell transplant and favorable co-occurring mutations confirmed sorafenib's benefit. Specifically, risk of an event was approximately two-fold higher in HAR /ITD+ patients who did not receive sorafenib (event-free survival from study entry: hazard ratio [HR] 2.37, 95% CI, 1.45 to 3.88, < .001, disease-free survival from complete remission: HR 2.28, 95% CI, 1.08 to 4.82, = .032, relapse risk from complete remission: HR 3.03, 95% CI 1.31 to 7.04, = .010).
CONCLUSION
Sorafenib can be safely added to conventional AML chemotherapy and may improve outcomes in pediatric HAR /ITD+ AML.
目的
高等位基因比（HAR）/插入缺失（ITD）（AR>0.4）突变与儿科急性髓细胞白血病（AML）的不良预后相关。COG AAML1031 研究了在该人群中添加多激酶酪氨酸激酶抑制剂索拉非尼作为标准化疗的辅助治疗以及单药维持治疗的可行性和疗效。
材料和方法
患者分为三个队列进行治疗。初始安全性阶段确定了索拉非尼的最大耐受剂量，起始于诱导期 2。队列 2 和 3 在诱导期和单药维持期添加索拉非尼。临床结果分析仅限于队列 2/3 中的 n=72 例患者，并与接受相同化疗但未接受索拉非尼的 n=76 例 HAR/ITD+AML 患者进行比较。对部分患者进行了索拉非尼药代动力学和血浆抑制活性检测。
结果
索拉非尼的最大耐受剂量为 200mg/m，每日一次；剂量限制毒性包括皮疹（n=2；1 级 3 级和 1 级 2 级）、2 级手足综合征和 3 级发热。药代动力学/血浆抑制活性数据表明，测量的血浆浓度足以抑制磷酸化 FLT3。尽管在队列 2 和 3 中索拉非尼治疗的结果更好，但接受索拉非尼治疗的患者比对照组更频繁地进行造血干细胞移植。考虑到造血干细胞移植和有利共存突变的多变量分析证实了索拉非尼的益处。具体来说，未接受索拉非尼治疗的 HAR/ITD+患者发生事件的风险大约增加两倍（从研究入组开始的无事件生存：风险比[HR]2.37，95%CI，1.45 至 3.88，<0.001，从完全缓解的无病生存：HR 2.28，95%CI，1.08 至 4.82，=0.032，从完全缓解的复发风险：HR 3.03，95%CI，1.31 至 7.04，=0.010）。
结论
索拉非尼可安全添加到常规 AML 化疗中，并可能改善儿科 HAR/ITD+AML 患者的预后。
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