ImportanceIn 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.ObjectiveTo compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL.Design, Setting, and ParticipantsGlobal 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.InterventionPatients 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 MeasuresThe 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.ResultsOf 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 RelevancePonatinib 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 RegistrationClinicalTrials.gov Identifier: NCT03589326

中文翻译：

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帕纳替尼与伊马替尼在费城染色体阳性急性淋巴细胞白血病一线治疗中的比较


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 酪氨酸激酶抑制剂获得性耐药而导致疾病进展的情况很常见。 Ponatinib 抑制 BCR::ABL1 和所有单突变变异体，包括 T315I。目的比较前线 ponatinib 与伊马替尼治疗新诊断 Ph+ ALL 的成人。设计、环境和参与者针对 18 岁成人的全球注册、3 期、开放标签试验或新诊断为 Ph+ ALL 的老年人。从2019年1月到2022年5月，77个中心的符合条件的患者被随机分配至普纳替尼（30毫克/天）或伊马替尼（600毫克/天），接受降低强度化疗，然后在周期后接受单药普纳替尼或伊马替尼审判第20阶段。该分析的最后一次随访日期是 2022 年 8 月 12 日。 干预患者接受 ponatinib，30 mg/d 或 imatinib，600 mg/d，并进行降低强度化疗，然后在第 20 个周期后接受单药 ponatinib 或imatinib达到微小残留病（MRD）阴性完全缓解后，普纳替尼剂量减少至 15 mg。主要结果和措施本次中期分析的主要终点是 MRD 阴性完全缓解（≤0.01% BCR::ABL1 [MR4] ] 通过逆转录酶定量聚合酶链反应进行集中评估），在第 3 周期结束时完全缓解维持至少 4 周。关键的次要终点是无事件生存期。结果 245 名随机患者（中位年龄 54 岁） ; 133 例 [54.3%] 女性）、232 例（普纳替尼，n = 154；伊马替尼，n = 78）经中心实验室验证具有 p190 或 p210 优势亚型的人进行了主要终点分析。 普纳替尼 (34.4% [53/154]) 与伊马替尼 (16.7% [13/78]) 的 MRD 阴性完全缓解率（主要终点）显着更高（风险差异，0.18 [95% CI，0.06-0.29] ]; P = .002)。在数据截止时，无事件生存率未达到预先指定的事件数。帕纳替尼组未达到中位无事件生存期，伊马替尼组为 29 个月。治疗组之间最常见的不良事件相似。动脉闭塞事件很少见，且组间具有可比性（帕纳替尼，2.5%；伊马替尼，1.2%）。 结论和相关性 成人中，帕纳替尼与降低强度化疗联合使用时，诱导结束时 MRD 阴性完全缓解率优于伊马替尼新诊断为 Ph+ ALL。普纳替尼的安全性与伊马替尼相当。试验注册临床试验。政府标识符：NCT03589326