asciminib同时靶向作用于天然和突变的BCR-ABL1,包括看门基因(gatekeeper)T315I突变体.
asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant.
asciminib用于费城染色体阳性白血病患者的安全性和抗白血病活性尚未明确.
the safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown.
在这项1期剂量递增研究中,我们纳入了141例慢性期和9例加速期慢性髓系白血病(CML)患者,这些患者既往对至少两种ATP竞争性酪氨酸激酶抑制剂(TKI)耐药或发生不可接受的副作用.
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).
本试验的主要目的是确定asciminib的最大耐受剂量或推荐剂量(或这两者).
the primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib.
asciminib每日给药1次或2次(每次剂量为10~200mg).
asciminib was administered once or twice daily (at doses of 10 to 200 mg).
中位随访时间为14个月.
the median follow-up was 14 months.
患者既往接受过大量治疗,70%(105/150例患者)既往接受过至少3种TKI治疗.
patients were heavily pretreated; 70 % (105 of 150 patients) had received at least three TKIs.
本试验未达到asciminib的最大耐受剂量.
the maximum tolerated dose of asciminib was not reached.
在慢性期CML患者中,基线时有血液学复发的34例(92%)患者达到了血液学完全缓解;基线时无细胞遗传学完全缓解的31例患者(54%)达到了细胞遗传学完全缓解.
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.
截至12个月时,在可评价的患者中,有48%达到或维持主要分子学缓解,包括被视为对普纳替尼(ponatinib)耐药或发生不可接受的副作用的14例患者中的8例(57%).
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.
截至12个月时,在基线时有T315I突变的患者中,有5例(28%)达到或维持主要分子学缓解.
a major molecular response was achieved or maintained by 12 months in 5 patients (28 %) with a T315I mutation at baseline.
临床缓解持久,44例患者中有40例维持主要分子学缓解.
clinical responses were durable; a major molecular response was maintained in 40 of 44 patients.
剂量限制性毒性作用包括无症状的脂肪酶水平升高和临床胰腺炎.
dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis.
常见不良事件包括疲劳,头痛,关节痛,高血压和血小板减少.
common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia.
在既往对TKI耐药或发生不可接受的副作用,并且接受过大量治疗的CML患者(包括普纳替尼治疗失败的患者和有T315I突变的患者)中,asciminib有活性(由诺华制药资助;在ClinicalTrials.gov注册号为NCT02081378).
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.)
在费城染色体(Ph)阳性的慢性髓系白血病(CML)患者中,酪氨酸激酶抑制剂(TKI)治疗失败的原因可能是患者对TKI耐药或发生不可接受的副作用,或两者兼有.
failure of tyrosine kinase inhibitor (TKI) therapy in patients with Philadelphia chromosome (Ph) -positive chronic myeloid leukemia (CML) may result from resistance to or unacceptable side effects from the drug or both.
目前已获批准的TKI主要靶向作用于BCR-ABL1的ATP结合位点,大约一半的临床耐药与激酶这一区域发生突变相关,突变会导致构象改变,从而使TKI失去活性1-6.
currently approved TKIs mainly target the ATP-binding site of BCR-ABL1, and approximately half of clinical resistance is associated with the acquisition of mutations in this region of the kinase, resulting in conformational changes that render TKIs inactive.1-6
据报道发生于约20%突变患者的看门基因T315I突变特别值得关注,因为它与除普纳替尼之外目前临床上所有TKI的耐药相关7-9.
the " gatekeeper " T315I mutation, reported in approximately 20 % of patients with mutations, is of particular concern because it is associated with resistance to all clinically available TKIs except ponatinib.7-9
约25%的患者使用TKI后会发生不可接受的副作用,而且我们越来越认识到接受第二代和第三代TKI治疗的患者有发生血管和肺部毒性作用的风险10-14.
unacceptable side effects from TKIs also occur in approximately 25 % of patients, with increasing recognition that patients receiving second- and third-generation TKIs are at risk for vascular and pulmonary toxic effects.10-14
asciminib(ABL001)是一种口服用药的强效特异性BCR-ABL1抑制剂,它与目前已批准的ABL1激酶抑制剂不同,因为它不与激酶的ATP结合位点相结合.
asciminib (ABL001) is a potent, specific, orally bioavailable BCR-ABL1 inhibitor that is distinct from approved ABL1 kinase inhibitors in that it does not bind to the ATP-binding site of the kinase.
相反,asciminib起到别构抑制剂的作用,它与激酶结构域中一个位点的空口袋相结合,而该口袋正常情况下是由ABL1的豆蔻酰化N-末端(该基序是别构负性调节元件,ABL1与BCR融合后丧失)占据(图1).
in contrast, asciminib acts as an allosteric inhibitor and engages a vacant pocket at a site of the kinase domain normally occupied by the myristoylated N-terminal of ABL1 - a motif that serves as an allosteric negative regulatory element lost on fusion of ABL1 to BCR (Figure 1).
通过结合豆蔻酰位点,asciminib可模拟豆蔻酸盐的作用,恢复对激酶活性的抑制.
by binding the myristoyl site, asciminib mimics myristate and restores inhibition of kinase activity.
由于豆蔻酰口袋的独特构象,asciminib仅对ABL1(以及推测对ABL2激酶)具有高选择性,并且对未突变的BCR-ABL1和临床观察到的所有ATP位点突变(包括T315I)具有较低的纳摩尔范围的活性15,16.
owing to the distinct conformation of the myristoyl pocket, asciminib has high selectivity for only ABL1 and, hypothetically, ABL2 kinases, with low-nanomolar-range activity against unmutated BCR-ABL1 and all clinically observed ATP-site mutants, including T315I.15,16
我们假设在已批准的多种TKI治疗失败的CML患者中,asciminib可能使患者达到有临床意义的缓解.
we hypothesized that asciminib may produce clinically significant responses in patients with CML in whom multiple approved TKIs have failed.