High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses
High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses
复制标题
DOI：
10.1038/leu.2012.105
复制
发表时间：
2012-11-01
期刊：
影响因子：
11.4
通讯作者：
Burchert, A.
中科院分区：
文献类型：
--
作者：
Metzelder, S. K.;Schroeder, T.;Burchert, A.
初步证据表明，多激酶抑制剂索拉非尼在FLT 3-ITD阳性（FLT 3-ITD）急性髓性白血病（AML）中具有临床活性。然而，可实现的缓解的质量和可持续性以及影响索拉非尼单药治疗结果的临床变量在很大程度上是不确定的。为了解决这些问题，我们在23个中心的65例FLT 3-ITD AML患者中评估了索拉非尼单药治疗。除两名患者外，所有患者均在中位三个化疗周期后复发或化疗难治。29例患者（45%）既往接受过异基因干细胞移植（allo-SCT）。记录的最佳缓解分别为：24例患者（37%）血液学缓解，5例患者（8%）骨髓缓解，15例患者（23%）完全缓解（伴或不伴外周血细胞计数正常化），10例患者（15%）分子学缓解伴FLT 3-ITD mRNA检测不到。17例既往无allo-SCT的患者（47%）在中位治疗持续时间136天（范围56-270天）后出现索拉非尼耐药。相比之下，allo-SCT患者发生索拉非尼耐药的频率较低（38%），且明显较晚（197天，范围38-225天; P = 0.03）。持续缓解仅见于allo-SCT队列。因此，索拉非尼单药治疗在FLT 3-ITD AML中具有显著活性，并可与同种异体免疫作用协同作用以诱导持久缓解。
Preliminary evidence suggests that the multikinase inhibitor sorafenib has clinical activity in FLT3-ITD-positive (FLT3-ITD) acute myeloid leukemia (AML). However, the quality and sustainability of achievable remissions and clinical variables that influence the outcome of sorafenib monotherapy are largely undefined. To address these questions, we evaluated sorafenib monotherapy in 65 FLT3-ITD AML patients treated at 23 centers. All but two patients had relapsed or were chemotherapy-refractory after a median of three prior chemotherapy cycles. Twenty-nine patients (45%) had undergone prior allogeneic stem cell transplantation (allo-SCT). The documented best responses were: hematological remission in 24 patients (37%), bone marrow remission in 5 patients (8%), complete remission (with and without normalization of peripheral blood counts) in 15 patients (23%) and molecular remission with undetectable FLT3-ITD mRNA in 10 patients (15%), respectively. Seventeen of the patients without prior allo-SCT (47%) developed sorafenib resistance after a median treatment duration of 136 days (range, 56-270 days). In contrast, allo-SCT patients developed sorafenib resistance less frequently (38%) and significantly later (197 days, range 38-225 days; P = 0.03). Sustained remissions were seen exclusively in the allo-SCT cohort. Thus, sorafenib monotherapy has significant activity in FLT3-ITD AML and may synergize with allogeneic immune effects to induce durable remissions.