Asciminib可有效治疗ABL激酶抑制剂无效的慢性髓系白血病
作者：
小柯机器人 发布时间：2019/12/17 16:37:59
南澳大利亚健康和医学研究所Timothy P. Hughes研究团队取得一项新突破。他们发现Asciminib可有效治疗ABL激酶抑制剂治疗失败的慢性髓系白血病。该项研究成果发表在2019年12月12日出版的《新英格兰医学杂志》上。
Asciminib是一种变构抑制剂，它结合BCR-ABL1蛋白的肉豆蔻酰基位点，通过不同于其他ABL激酶抑制剂的机制将BCR-ABL1锁定为非活性构象。Asciminib以野生和突变的BCR-ABL1为靶点，包括T315I突变株。但Asciminib在费城染色体阳性白血病患者中的安全性与抗白血病活性尚未清楚。
在第一阶段的剂量递增研究中，研究组招募了141名慢性期和9名加速期的慢性髓细胞白血病（CML）患者，他们此前至少对两种ATP竞争性酪氨酸激酶抑制剂（TKIs）耐药或有较大的副作用。主要目的是确定Asciminib的最大耐受剂量或推荐剂量。
所有患者均接受了大量的预治疗。70%的患者至少接受了3次TKI。未达到Asciminib的最大耐受剂量。对于慢性期的CML患者，92%血液学复发的患者获得完全的血液学缓解，54%基线时没有完全的细胞遗传学反应的患者获得了完全的血液学缓解。
48%的患者在12个月内获得或维持了主要的分子反应，其中57%对普纳替尼耐药或有较大的副作用。28%的T315I突变患者在12个月内获得或维持了主要的分子反应。临床反应持久，44例患者中有40例维持了主要分子反应。剂量限制性毒性作用主要包括脂肪酶水平无症状升高和临床胰腺炎。常见的不良反应包括疲劳、头痛、关节痛、高血压和血小板减少。
Asciminib对重度预治疗的CML患者有一定疗效，这些患者对TKIs耐药或有较大毒副作用，包括普纳替尼治疗失败和T315I突变的患者。
附：英文原文
Title: Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure
Author: Timothy P. Hughes, M.D.,, Michael J. Mauro, M.D.,, Jorge E. Cortes, M.D.,, Hironobu Minami, M.D.,, Delphine Rea, M.D.,, Daniel J. DeAngelo, M.D., Ph.D.,, Massimo Breccia, M.D.,, Yeow-Tee Goh, M.D.,, Moshe Talpaz, M.D.,, Andreas Hochhaus, M.D.,, Philipp le Coutre, M.D.,, Oliver Ottmann, M.D.,, Michael C. Heinrich, M.D.,, Juan L. Steegmann, M.D., Ph.D.,, Michael W.N. Deininger, M.D., Ph.D.,, Jeroen J.W.M. Janssen, M.D., Ph.D.,, Francois-Xavier Mahon, M.D.,, Yosuke Minami, M.D., Ph.D.,, David Yeung, M.D.,, David M. Ross, M.B., B.S., Ph.D.,, Martin S. Tallman, M.D.,, Jae H. Park, M.D.,, Brian J. Druker, M.D.,, David Hynds, M.S.,, Yuyan Duan, Ph.D.,, Christophe Meille, Ph.D.,, Florence Hourcade-Potelleret, Ph.D.,, K. Gary Vanasse, M.D.,, Fabian Lang, M.D.,, and Dong-Wook Kim, M.D., Ph.D.
Issue&Volume: 2019-12-11
Abstract:
Background
Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome–positive leukemia are unknown.
Methods
In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months.
Results
Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia.
Conclusions
Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.)
DOI: 10.1056/NEJMoa1902328
Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1902328
