Division of Hematology, First Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
Int J Hematol. 2012 Oct;96(4):485-91. doi: 10.1007/s12185-012-1165-z. Epub 2012 Sep 6.
We conducted a phase 1 study of a combination of gemtuzumab ozogamicin (GO) plus conventional chemotherapy in elderly patients (≥ 65 years old) with relapsed or refractory CD33-positive acute myeloid leukemia (AML). Patients received a standard dose of enocitabine (200 mg/m² × 8 days) and daunorubicin (30 mg/m² × days 1-3) plus an escalating dose of GO (1.5-5 mg/m² on day 4). The dose escalation of GO was done according to a standard 3 + 3 design following a modified Fibonacci sequence. No dose-limiting toxicities were observed in three patients (median age, 71) at level 1 (1.5 mg/m²) or in three patients (median age, 73) at level 2 (3 mg/m²). Neither veno-occlusive diseases nor sinusoidal obstructive syndromes were noted at either level. However, as GO was withdrawn from the US market in June 2010, based on a randomized study in newly diagnosed AML, we decided not to proceed to the level 3 (5 mg/m²) in order to avoid possibly more severe adverse effects, and also because all six patients experienced grade 4 myelosuppression, with complete remission in three. This study showed that 3 mg/m² of GO in combination with enocitabine and daunorubicin may be a recommendable dose for a phase 2 study in Japanese elderly patients with CD33-positive AML. The study was registered at the University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( http://www.umin.ac.jp/ctr/ ) as UMIN000002603.
我们进行了一项 1 期研究，在复发或难治性 CD33 阳性急性髓系白血病（AML）老年患者（≥65 岁）中联合使用吉妥珠单抗奥佐米星（GO）和常规化疗。患者接受标准剂量依托泊苷（200 mg/m²×8 天）和柔红霉素（30 mg/m²×天 1-3），加用递增剂量 GO（第 4 天 1.5-5 mg/m²）。GO 的剂量递增根据改良 Fibonacci 序列的标准 3 + 3 设计进行。在 1 级（1.5 mg/m²）或 2 级（3 mg/m²）的 3 名患者（中位年龄为 71 岁）或 3 名患者（中位年龄为 73 岁）中未观察到剂量限制毒性。在任何剂量水平均未观察到静脉闭塞病或窦阻塞综合征。然而，由于 GO 于 2010 年 6 月因在新诊断 AML 中的一项随机研究而退出美国市场，我们决定不进行 3 级（5 mg/m²），以避免可能更严重的不良反应，而且所有 6 名患者均经历了 4 级骨髓抑制，3 名患者完全缓解。这项研究表明，GO 联合依托泊苷和柔红霉素 3 mg/m²可能是日本 CD33 阳性 AML 老年患者进行 2 期研究的推荐剂量。该研究在大学医院医疗信息网络（UMIN）临床试验注册处（http://www.umin.ac.jp/ctr/）进行了注册，注册号为 UMIN000002603。
