Schimmer Aaron D, O'Brien Susan, Kantarjian Hagop, Brandwein Joseph, Cheson Bruce D, Minden Mark D, Yee Karen, Ravandi Farhad, Giles Francis, Schuh Andre, Gupta Vikas, Andreeff Michael, Koller Charles, Chang Hong, Kamel-Reid Suzanne, Berger Mark, Viallet Jean, Borthakur Gautam
Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.
Clin Cancer Res. 2008 Dec 15;14(24):8295-301. doi: 10.1158/1078-0432.CCR-08-0999.
The outcome of patients with refractory leukemia and myelodysplasia is poor, and new therapies are needed. The antiapoptotic proteins of the Bcl-2 family are overexpressed in these malignancies and are potential therapeutic targets. Therefore, we conducted a phase I clinical trial of the small-molecule pan-Bcl-2 inhibitor, obatoclax mesylate, in patients with refractory leukemia and myelodysplasia to assess its safety and define its optimal dose.
Forty-four patients with refractory leukemia or myelodysplasia were treated with obatoclax mesylate by continuous intravenous infusion at increasing doses and frequencies.
A total of 306 infusions of obatoclax mesylate were administered with a median of 5 infusions per patient. The study drug was well tolerated up to the highest dose planned without dose-limiting toxicity. Grade 1/2 central nervous system symptoms were the most common adverse events attributable to the study drug. One patient with acute myeloid leukemia with mixed lineage leukemia t(9;11) rearrangement achieved a complete remission, which lasted 8 months. Three of 14 patients with myelodysplasia showed hematologic improvement with RBC or platelet transfusion independence.
Obatoclax mesylate is well tolerated and these results support its further investigation in patients with leukemia and myelodysplasia.
难治性白血病和骨髓增生异常综合征患者的预后较差，需要新的治疗方法。Bcl-2家族的抗凋亡蛋白在这些恶性肿瘤中过表达，是潜在的治疗靶点。因此，我们开展了一项针对难治性白血病和骨髓增生异常综合征患者的I期临床试验，以评估小分子泛Bcl-2抑制剂甲磺酸奥巴托克斯的安全性并确定其最佳剂量。
44例难治性白血病或骨髓增生异常综合征患者接受了甲磺酸奥巴托克斯的持续静脉输注治疗，剂量和频率逐渐增加。
共进行了306次甲磺酸奥巴托克斯输注，每位患者的输注中位数为5次。在计划的最高剂量下，研究药物耐受性良好，无剂量限制毒性。1/2级中枢神经系统症状是与研究药物相关的最常见不良事件。1例伴有混合谱系白血病t(9;11)重排的急性髓系白血病患者实现了完全缓解，持续8个月。14例骨髓增生异常综合征患者中有3例出现血液学改善，不再需要输注红细胞或血小板。
甲磺酸奥巴托克斯耐受性良好，这些结果支持对其在白血病和骨髓增生异常综合征患者中进行进一步研究。
