Department of Oncology/Haematology, bone marrow transplantation with section pneumology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Department of Internal Medicine V, University Hospital of Heidelberg, Heidelberg, Germany.
Br J Haematol. 2015 Jun;169(5):694-700. doi: 10.1111/bjh.13353. Epub 2015 Mar 29.
Acute myeloid leukaemia (AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside (Ara-C)/daunorubicin induction (7+3) followed by three cycles of intermediate-dose Ara-C consolidation in 22 AML patients with activating FLT3 mutations. Sunitinib was added at predefined dose levels and as maintenance therapy for 2 years. At dose level 1, sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose-limiting toxicity (DLT), prolonged haemotoxicity and hand-foot syndrome. At dose level -1, sunitinib 25 mg was restricted to days 1-7 of each chemotherapy cycle. One DLT was observed in six evaluable patients. Six additional patients were treated in an extension phase. Thirteen of 22 patients (59%; 8/14 with FLT3-internal tandem duplication and 5/8 with FLT3-tyrosine kinase domain) achieved a complete remission/complete remission with incomplete blood count recovery. For the 17 patients included at the lower dose level, median overall, relapse-free and event-free survival were 1·6, 1·0 and 0·4 years, respectively. Four out of five analysed patients with relapse during maintenance therapy lost their initial FLT3 mutation, suggesting outgrowth of FLT3 wild-type subclones.
FLT3 突变的急性髓系白血病（AML）在老年患者中的预后较差。联合使用 FLT3 抑制剂和标准化疗的治疗方法尚未得到广泛研究。因此，我们启动了一项临床试验，研究了 22 例携带激活型 FLT3 突变的 AML 患者，这些患者接受阿糖胞苷（Ara-C）/柔红霉素诱导（7+3）化疗，随后进行三个周期的中剂量 Ara-C 巩固治疗，并添加舒尼替尼作为治疗方案。舒尼替尼预先设定剂量水平，并作为维持治疗，持续 2 年。在剂量水平 1 时，每天连续服用舒尼替尼 25mg（从第 1 天开始），导致 2 例患者出现剂量限制毒性（DLT），表现为血液毒性延长和手足综合征。在剂量水平-1 时，舒尼替尼限制在每个化疗周期的第 1-7 天使用。在 6 例可评估患者中观察到 1 例 DLT。6 例额外患者进入扩展阶段治疗。22 例患者中的 13 例（59%；14 例 FLT3 内部串联重复和 8 例 FLT3 酪氨酸激酶结构域突变患者中有 5 例）获得完全缓解/完全缓解伴不完全血细胞计数恢复。对于接受较低剂量水平治疗的 17 例患者，中位总生存期、无复发生存期和无事件生存期分别为 1.6 年、1.0 年和 0.4 年。在维持治疗期间复发的 5 例患者中有 4 例丢失了最初的 FLT3 突变，提示 FLT3 野生型亚克隆的生长。
