Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia.
Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia.
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DOI：
10.1056/nejmoa1509981
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发表时间：
2016-01-28
期刊：
影响因子：
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通讯作者：
Furman RR
中科院分区：
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作者：
Byrd JC;Harrington B;O'Brien S;Jones JA;Schuh A;Devereux S;Chaves J;Wierda WG;Awan FT;Brown JR;Hillmen P;Stephens DM;Ghia P;Barrientos JC;Pagel JM;Woyach J;Johnson D;Huang J;Wang X;Kaptein A;Lannutti BJ;Covey T;Fardis M;McGreivy J;Hamdy A;Rothbaum W;Izumi R;Diacovo TG;Johnson AJ;Furman RR
伊曲替尼对布鲁顿酪氨酸激酶（Btk）的不可逆抑制代表了慢性淋巴细胞白血病（CLL）的显著治疗进展。然而，伊布替尼也不可逆地抑制替代激酶靶点，这可能会损害其治疗指数。Acalabrutinib（ACP-196）是一种选择性更高的不可逆Btk抑制剂，专门设计用于改善第一代Btk抑制剂的安全性和有效性。61例复发性CLL患者在1-2期多中心研究中接受治疗，该研究旨在评估口服acalabrutinib的安全性、疗效、药代动力学和药效学。患者在研究的剂量递增部分接受100 - 400 mg acalabrutinib每日一次连续治疗，在扩展部分接受100 mg每日两次连续治疗。患者人口统计学资料包括中位年龄62岁;中位3种既往治疗; 31% del（17）（p13.1）和75%未突变免疫球蛋白重链可变基因。未发生剂量限制性毒性。最常见的不良事件是头痛（43%），腹泻（39%）和体重增加（26%）。大多数不良事件为1-2级。在中位随访14.3个月时，最佳总体缓解率为95%，包括85%的部分缓解，10%的淋巴细胞增多症部分缓解和5%的疾病稳定。在del（17）（p13.1）患者中，最佳总体缓解率为100%。未发生Richter转化病例，仅发生1例CLL进展。Acalabrutinib是一种高选择性Btk抑制剂，可为复发性CLL患者（包括del（17）患者）提供有效且耐受性良好的治疗（p13.1）。
Irreversible inhibition of Bruton tyrosine kinase (Btk) by ibrutinib represents a significant therapeutic advance for chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromise its therapeutic index. Acalabrutinib (ACP-196) is a more selective irreversible Btk inhibitor specifically designed to improve upon the safety and efficacy of first generation Btk inhibitors. Sixty-one patients with relapsed CLL were treated in a phase 1–2 multicenter study designed to assess the safety, efficacy, pharmacokinetics and pharmacodynamics of oral acalabrutinib. Patients were continuously treated with acalabrutinib 100 to 400 mg once daily in the dose-escalation portion of the study, and 100 mg twice daily in the expansion portion. Patient demographics include a median age of 62 years; median of 3 prior therapies; 31% del(17)(p13.1) and 75% unmutated immunoglobulin heavy chain variable genes. No dose-limiting toxicities occurred. The most common adverse events observed were headache (43%), diarrhea (39%) and increased weight (26%). Most adverse events were Grade 1–2. At a median follow-up of 14.3 months, the best overall response rate was 95%, including 85% partial response, 10% partial response with lymphocytosis and 5% stable disease. In patients with del(17)(p13.1), the best overall response was 100%. No cases of Richter’s transformation and only 1 CLL progression have occurred. Acalabrutinib is a highly selective Btk inhibitor that provides effective and well tolerated treatment for patients with relapsed CLL, including those with del(17)(p13.1).