Phase I/II study of dasatinib in combination with decitabine in patients with accelerated or blast phase chronic myeloid leukemia
Phase I/II study of dasatinib in combination with decitabine in patients with accelerated or blast phase chronic myeloid leukemia
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DOI：
10.1002/ajh.25939
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发表时间：
2020-08-12
影响因子：
12.8
通讯作者：
Cortes, Jorge
中科院分区：
文献类型：
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作者：
Abaza, Yasmin;Kantarjian, Hagop;Cortes, Jorge
晚期慢性粒细胞白血病（CML）的治疗仍然不能令人满意。单一药物酪氨酸激酶抑制剂在这种情况下具有适度和短暂的活性。我们进行了一项I/II期研究，以确定达沙替尼和地西他滨联合治疗晚期CML患者的安全性和有效性。研究了两种不同的给药方案，地西他滨起始剂量为10 mg/m2或20 mg/m2，每日1次，持续10天，加达沙替尼100 mg，每日1次。目标剂量水平为地西他滨10 mg/m2或20 mg/m2每日一次，持续10天，加达沙替尼140 mg每日一次。30例患者入组，包括7例加速期CML，19例急变期CML，4例费城染色体阳性急性髓性白血病。在任一方案的起始剂量水平下均未观察到剂量限制性毒性。28例患者报告了≥ 3级治疗后出现的血液学不良事件。13例患者（48%）实现了主要血液学缓解，6例（22%）实现了次要血液学缓解，其中44%的患者实现了主要细胞遗传学缓解，33%实现了主要分子学缓解。中位总生存期（OS）为13.8个月，与无应答者相比，血液学应答患者的OS显著更高（未达到vs 4.65个月;P <0.001）。地西他滨联合达沙替尼治疗晚期CML安全有效。使用这种组合的进一步研究是必要的。
Treatment of advanced-phase chronic myeloid leukemia (CML) remains unsatisfactory. Single-agent tyrosine kinase inhibitors have modest and short-lived activity in this setting. We conducted a phase I/II study to determine safety and efficacy of the combination of dasatinib and decitabine in patients with advanced CML. Two different dose schedules were investigated with a starting decitabine dose of either 10 mg/m(2)or 20 mg/m(2)daily for 10 days plus dasatinib 100 mg daily. The target dose level was decitabine 10 mg/m(2)or 20 mg/m(2)daily for 10 days plus dasatinib 140 mg daily. Thirty patients were enrolled, including seven with accelerated-phase CML, 19 with blast-phase CML, and four with Philadelphia-chromosome positive acute myeloid leukemia. No dose-limiting toxicity was observed at the starting dose level with either schedule. Grade >= 3 treatment emergent hematological adverse events were reported in 28 patients. Thirteen patients (48%) achieved a major hematologic response and six (22%) achieved a minor hematologic response, with 44% of these patients achieving a major cytogenetic response and 33% achieving a major molecular response. Median overall survival (OS) was 13.8 months, with significantly higher OS among patients who achieved a hematologic response compared to non-responders (not reached vs 4.65 months;P < .001). Decitabine plus dasatinib is a safe and active regimen in advanced CML. Further studies using this combination are warranted.