Phase I study of sorafenib in patients with refractory or relapsed acute leukemias
Phase I study of sorafenib in patients with refractory or relapsed acute leukemias
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DOI：
10.3324/haematol.2010.030452
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Cortes, Jorge E.
中科院分区：
文献类型：
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作者：
Borthakur, Gautam;Kantarjian, Hagop;Cortes, Jorge E.
索拉非尼是一种多激酶抑制剂，具有抗FMS样酪氨酸激酶3、内部串联重复突变和Raf激酶等活性。索拉非尼对晚期骨髓增生异常综合征和复发或难治性急性白血病患者进行I期剂量递增研究。设计与方法50例患者接受两种不同方案中的一种；方案A：每天一次或两次，每周5天，共21天周期；方案B：每天一次或两次，每21天14天。剂量限制毒性为3/4级高血压、高胆红素血症和淀粉酶升高。恶性血液病的推荐II期剂量为每天两次，400 mg。结果5例(10%)患者获得了完全缓解或完全缓解，但血小板未完全恢复(均为FMS样酪氨酸激酶3内部串联复制)。另有17名(34%)患者的骨髓和/或外周血母细胞显著减少(均为FMS样酪氨酸激酶3-内部串联复制)。其中11例(包括3例完全缓解/完全缓解但未完全恢复)持续2个周期或以上。结论索拉非尼对急性髓系白血病患者，特别是具有EMS样酪氨酸激酶3内部串联重复突变的患者，有必要进行进一步的研究，包括索拉非尼联合用药。(ClinicalTrials.gov标识：NCT00217646)
BackgroundSorafenib is a multi-kinase inhibitor with activity against fms-like tyrosine kinase 3 with internal tandem duplication mutation and Raf kinase among others. A phase I dose escalation study of sorafenib was conducted in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias.Design and MethodsFifty patients received one of two different schedules; Schedule "A": once or twice daily, five days per week, every week for a 21 day cycle, and Schedule "B": once or twice daily, for 14 days every 21 days. Dose limiting toxicities were grade 3/4 hypertension, hyperbilirubinemia, and amylase elevation. The recommended phase II dose in hematologic malignancies is 400 mg twice daily for both schedules.ResultsComplete remissions or complete remissions with incomplete recovery of platelets were achieved in 5 (10%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Significant reduction in bone marrow and/or peripheral blood blasts was seen in an additional 17 (34%) patients (all with fms-like tyrosine kinase 3-internal tandem duplication). Eleven of these responses (including 3 complete remissions/complete remissions with incomplete recovery) lasted for 2 cycles or beyond. In conclusion, sorafenib is active and well tolerated in acute myelogenous leukemia with fms-like tyrosine kinase 3 internal tandem duplication mutation.ConclusionsAdditional studies of sorafenib in patients with acute myelogenous leukemia, particularly those with Ems-like tyrosine kinase 3 internal tandem duplication, are warranted, including sorafenib-based combinations. (ClinicalTrials.gov Identifier: NCT00217646)