Department of Hematology/Oncology, Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, WA.
Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
J Clin Oncol. 2020 Jul 1;38(19):2170-2177. doi: 10.1200/JCO.19.03306. Epub 2020 May 13.
Effective regimens are needed for children with relapsed acute myeloid leukemia (AML). AAML1421 is a phase I/II study of CPX-351, a liposomal preparation of daunorubicin and cytarabine. AAML1421 sought to determine the recommended phase II dose (RP2D) of CPX-351 and the response rate after up to 2 cycles of therapy.
Children > 1 and ≤ 21 years of age with relapsed/refractory AML were eligible for dose finding; those in first relapse were eligible for the efficacy phase. Dose-limiting toxicity (DLT) assessment occurred during cycle 1. Two cycles of therapy were offered (cycle 1: CPX-351; cycle 2: FLAG [fludarabine 30 mg/m/dose on days 1-5; cytarabine 2,000 mg/m/dose on days 1-5; and granulocyte-colony stimulating factor 5 µg/kg/dose, days 1-5 and day 15 through absolute neutrophil count > 500/µL]). Response was assessed after each cycle.
Thirty-eight patients enrolled: 6 in the dose-finding phase and 32 in the efficacy phase. During dose finding, 1/6 patients experienced a DLT (grade 3 decrease in ejection fraction). The RP2D was 135 units/m on days 1, 3, and 5. Toxicities of grade ≥ 3 during cycle 1 included fever/neutropenia (45%), infection (47%), and rash (40%). There was no toxic mortality. Best responses included 20 complete response (CR; 54%), 5 CR with partial recovery of platelet count (CRp; 14%), and 5 CR with incomplete blood count recovery (14%). Twenty-one of 25 with CR/CRp had no detectable residual disease (RD; 84%) by flow cytometry. Hematopoietic stem cell transplantation (HSCT) was used as consolidation in 29/30 responders (96.7%); 20/25 (80%) had no RD before HSCT.
The RP2D of CPX-351 is 135 units/m/dose on days 1, 3, and 5. Toxicity was manageable, and protocol therapy was effective. Response rates are superior to prior published North American cooperative group clinical trials for children with AML in first relapse.
需要为复发急性髓系白血病（AML）患儿制定有效的治疗方案。AAML1421 是一项 CPX-351 的 I/II 期研究，CPX-351 是柔红霉素和阿糖胞苷的脂质体制剂。AAML1421 旨在确定 CPX-351 的 II 期推荐剂量（RP2D）以及最多 2 个疗程后的缓解率。
年龄＞1 岁且≤21 岁、复发/难治性 AML 患儿符合入组条件；初发复发的患儿符合疗效阶段的入组条件。在第 1 周期评估剂量限制毒性（DLT）。患儿接受 2 个周期的治疗（第 1 周期：CPX-351；第 2 周期：FLAG[氟达拉滨 30 mg/m/剂量，第 1-5 天；阿糖胞苷 2000 mg/m/剂量，第 1-5 天；粒细胞集落刺激因子 5 µg/kg/剂量，第 1-5 天和第 15 天，直至中性粒细胞绝对计数＞500/µL]）。每个周期后评估缓解情况。
38 例患儿入组：6 例在剂量探索阶段，32 例在疗效阶段。在剂量探索阶段，1/6 例患儿发生 DLT（射血分数下降 3 级）。CPX-351 的 RP2D 为 135 个单位/m，第 1、3 和 5 天用药。第 1 周期≥3 级的毒性包括发热/中性粒细胞减少（45%）、感染（47%）和皮疹（40%）。无治疗相关死亡。最佳缓解包括 20 例完全缓解（CR；54%）、5 例 CR 伴血小板计数部分恢复（CRp；14%）和 5 例 CR 伴不完全血细胞计数恢复（14%）。25 例 CR/CRp 中有 21 例（84%）通过流式细胞术检测到无残留疾病（RD）。29/30 例缓解者接受造血干细胞移植（HSCT）作为巩固治疗（96.7%）；20/25 例（80%）在 HSCT 前 RD 阴性。
CPX-351 的 RP2D 为 135 个单位/m，第 1、3 和 5 天用药。毒性可管理，且方案治疗有效。缓解率优于先前发表的北美合作组儿童 AML 初发复发的临床试验结果。
