达沙替尼是治疗费城染色体阳性（Ph ）急性白血病的有效方法，但有些患者会产生耐药性。达沙替尼和阿西米尼（BCR::ABL1 的变构抑制剂）联合治疗可能会加深疗效并防止达沙替尼耐药克隆的出现。在这项 1 期研究 (NCT03595017) 中，24 名成人患有 Ph 急性淋巴细胞白血病（ALL，n=22；p190，n=16；p210，n=6）和处于淋巴母细胞危象的慢性粒细胞白血病（CML-LBC，n= 2) 接受每日递增剂量的阿西米尼联合达沙替尼 140 mg 每日加泼尼松 60 mg/m2 每日治疗，以确定最大耐受剂量 (MTD)。 28 天诱导后，达沙替尼和阿西米尼无限期持续或直至造血干细胞移植。中位年龄为 64.5 岁（范围：33-85 岁；50% 65 岁）。阿西米尼的推荐 2 期剂量为每天 80 毫克，与达沙替尼和泼尼松联合使用。每日 160 mg 的剂量限制性毒性为无症状 3 级胰酶升高，无症状性胰腺炎。没有发生血管闭塞事件。在新发 ALL 患者中，第 28 天和第 84 天的完全血液学缓解率分别为 84% 和 100%。第 84 天时，100% 的患者实现完全细胞遗传学缓解，89% 的患者通过多色流式细胞术实现可测量的残留疾病阴性 (<0.01%)，74% 和 26% 的患者实现 BCR::ABL1 RT-PCR <0.1% 和 <0.01 %。达沙替尼和阿西米尼双重 BCR::ABL1 抑制对于新发 Ph ALL 患者来说是安全的，且具有令人鼓舞的活性。 ClinicalTrials.gov NCT02081378.版权所有 © 2024 美国血液学会。

Dasatinib is effective treatment for Philadelphia chromosome-positive (Ph+) acute leukemia but some patients develop resistance. Combination treatment with dasatinib and asciminib, an allosteric inhibitor of BCR::ABL1, may deepen responses and prevent the emergence of dasatinib-resistant clones. In this phase 1 study (NCT03595017), 24 adults with Ph+ acute lymphoblastic leukemia (ALL, n=22; p190, n=16; p210, n=6) and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC, n=2) were treated with escalating daily doses of asciminib in combination with dasatinib 140 mg daily plus prednisone 60 mg/m2 daily to determine the maximum tolerated dose (MTD). After a 28-day induction, dasatinib and asciminib continued indefinitely or until hematopoietic stem cell transplant. The median age was 64.5 years (range, 33-85; 50% ³65). The recommended phase 2 dose of asciminib was 80 mg daily in combination with dasatinib and prednisone. The dose limiting toxicity at 160 mg daily was asymptomatic grade 3 pancreatic enzyme elevation without symptomatic pancreatitis. There were no vaso-occlusive events. Among patients with de novo ALL, the complete hematologic remission rate at day 28 and 84 was 84% and 100%, respectively. At day 84, 100% of patients achieved complete cytogenetic remission, 89% achieved measurable residual disease negativity (<0.01%) by multicolor flow cytometry, and 74% and 26% achieved BCR::ABL1 RT-PCR <0.1% and <0.01%. Dual BCR::ABL1 inhibition with dasatinib and asciminib is safe with encouraging activity in patients with de novo Ph+ ALL. ClinicalTrials.gov NCT02081378.Copyright © 2024 American Society of Hematology.