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期刊来源：JAMA

原文链接：https://doi.org/10.1001/jama.2024.4783

摘要内容如下：

重要性

在新诊断的费城染色体阳性（pH+）急性淋巴细胞白血病（ALL）中，由于对第一代或第二代BCR：:ABL1酪氨酸激酶抑制剂的获得性耐药而导致的疾病进展是常见的。Ponatinib抑制BCR：:ABL1和所有单突变变异体，包括T315I。

目的

在新诊断为pH+ALL的成人患者中比较一线ponatinib与imatinib。

设计、设置和参与者

在18岁或以上新诊断为pH+ALL的成人中进行的全球注册、3期、开放标签试验。从2019年1月至2022年5月，77个地点的符合条件的患者以2:1的比例随机接受ponatinib（30 mg/d）或imatinib（600 mg/d）的低强度化疗，然后在试验的第20周期阶段后接受单药ponatinib或imatinib。本次分析的最后一次随访日期为2022年8月12日。

干预

患者接受ponatinib（30 mg/d）或imatinib（600 mg/d）降低强度化疗，然后在第20周期后接受单药ponatinib或imatinib。达到微小残留病（MRD）阴性完全缓解后，ponatinib剂量降至15 mg。

主要成果和措施

该中期分析的主要终点是MRD阴性完全缓解（通过逆转录定量聚合酶链反应集中评估≤0.01%BCR：:ABL1[MR4]），在第3周期结束时完全缓解至少维持4周。关键的次要终点是无事件生存率。

结果

在随机分组的245名患者中（中位年龄54岁；133[54.3%]女性），232（ponatinib，n=154；伊马替尼，n=78）经中心实验室验证具有p190或p210优势亚型的患者进行主要终点分析。与伊马替尼（16.7%[13/78]）相比，ponatinib（34.4%[53/154]）的MRD阴性完全缓解率（主要终点）显著较高（风险差异，0.18[95%CI，0.06-0.29]；P=.002）。在数据截止点，无事件生存率未达到预先指定的事件数量。ponatinib组的中位无事件生存期为29个月，而imatinib组的中位无事件生存期为29个月。治疗组之间最常见的不良事件相似。动脉闭塞事件很少发生，两组间具有可比性（ponatinib，2.5%；伊马替尼，1.2%）。

结论和相关性

在新诊断为pH+ALL的成人患者中，与伊马替尼联合低强度化疗相比，ponatinib在诱导结束时的MRD阴性完全缓解率更高。ponatinib的安全性与伊马替尼相当。

试用注册

ClinicalTrials.gov标识符：NCT03589326。

英文原文如下：

Abstracts

Importance  In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I.

Objective  To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL.

Design, Setting, and Participants  Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022.

Intervention  Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease-(MRD) negative complete remission.

Main Outcomes and Measures  The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase-quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival.

Results  Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%).

Conclusions and Relevance  Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib.

Trial Registration  ClinicalTrials.gov Identifier: NCT03589326.

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