Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands.
J Clin Oncol. 2013 Jul 1;31(19):2460-8. doi: 10.1200/JCO.2012.46.8280. Epub 2013 May 28.
Dasatinib is a potent BCR-ABL inhibitor with proven efficacy in adults with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) and in imatinib-resistant/intolerant disease. This phase I study of the Innovative Therapies for Children with Cancer Consortium assessed dasatinib safety and efficacy in pediatric patients.
Escalating once-daily dasatinib doses (60 to 120 mg/m(2)) were administered to children (n = 58) with (i) imatinib-pretreated CML or Philadelphia chromosome (Ph)-positive acute lymhoblastic leukemia (ALL) and (ii) treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML).
Dasatinib safety and efficacy profiles compared favorably with those in adults. The most common drug-related nonhematologic adverse events were nausea (31%, all grades; 2%, grade 3 to 4), headache (22%, 3%), diarrhea (21%, 0%), and vomiting (17%, 2%). Of 17 patients with CML-CP, 14 (82%) achieved complete cytogenetic response (CCyR) and eight (47%) achieved major molecular response. After ≥ 24 months of follow-up, median complete hematologic response (CHR) and major cytogenetic response (MCyR) durations were not reached. Of 17 patients with advanced-phase CML or Ph-positive ALL, six (35%) achieved confirmed CHR and 11 (65%) achieved CCyR. Median MCyR duration was 4.6 months (95% CI, 2.1 to 17.4 months). No patient with Ph-negative ALL or AML responded. Dasatinib pediatric pharmacokinetic parameters were comparable with those in adult studies, showing rapid absorption (time to reach maximum concentration, 0.5 to 6.0 hours) and elimination (mean half-life, 3.0 to 4.4 hours).
Dasatinib 60 mg/m(2) and 80 mg/m(2) once-daily dosing were selected for phase II studies in children with Ph-positive leukemias.
达沙替尼是一种强效的 BCR-ABL 抑制剂，已被证明在新诊断的慢性髓性白血病（CML）慢性期（CP）和伊马替尼耐药/不耐受疾病的成人患者中具有疗效。这项由儿童癌症创新疗法研究联盟进行的 I 期研究评估了达沙替尼在儿科患者中的安全性和疗效。
58 名（i）接受过伊马替尼预处理的 CML 或费城染色体（Ph）阳性急性淋巴细胞白血病（ALL）和（ii）治疗难治性 Ph 阴性 ALL 或急性髓细胞白血病（AML）的患儿接受了递增的每日一次达沙替尼剂量（60 至 120mg/m²）。
达沙替尼的安全性和疗效与成人患者相比具有优势。最常见的药物相关非血液学不良事件为恶心（31%，所有级别；2%，3 至 4 级）、头痛（22%，3%）、腹泻（21%，0%）和呕吐（17%，2%）。17 例 CML-CP 患者中，14 例（82%）达到完全细胞遗传学缓解（CCyR），8 例（47%）达到主要分子缓解。在≥24 个月的随访后，中位完全血液学缓解（CHR）和主要细胞遗传学缓解（MCyR）持续时间尚未达到。17 例晚期 CML 或 Ph 阳性 ALL 患者中，6 例（35%）达到确认的 CHR，11 例（65%）达到 CCyR。中位 MCyR 持续时间为 4.6 个月（95%CI，2.1 至 17.4 个月）。无 Ph 阴性 ALL 或 AML 患者有反应。达沙替尼儿科药代动力学参数与成人研究相似，表现为快速吸收（达到最大浓度的时间，0.5 至 6.0 小时）和消除（平均半衰期，3.0 至 4.4 小时）。
选择达沙替尼 60mg/m²和 80mg/m² 每日一次剂量用于 Ph 阳性白血病儿童的 II 期研究。
