Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Georgia Cancer Center, Augusta University, Augusta, Georgia, USA.
Cancer. 2024 Oct 1;130(19):3344-3352. doi: 10.1002/cncr.35384. Epub 2024 May 28.
Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome-positive leukemias. Herein, we report the long-term follow-up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase.
Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6-month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI.
Fifty-one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21-75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2-25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second-line TKI (n = 34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6-month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24-month event-free survival rate was 97%. After a median follow-up of 128 months, the 10-year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%).
Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio-/vaso-occlusive and other severe toxicities.
Ponatinib 是一种第三代 BCR::ABL1 酪氨酸激酶抑制剂（TKI），在费城染色体阳性白血病中具有强大的活性。在此，我们报告了 ponatinib 在慢性期慢性髓性白血病的 2 期试验的长期随访结果。
患者接受 ponatinib 30 至 45 mg/天。主要终点是 6 个月完全细胞遗传学缓解（CCyR）率。由于心血管毒性的风险，该研究于 2014 年 6 月进行，要求患者改变 TKI。
51 例患者接受 ponatinib 治疗（中位剂量，45 mg/天）。中位年龄为 48 岁（范围，21-75）；30 例（59%）有基线心血管合并症。中位治疗持续时间为 13 个月（范围，2-25）。14 例（28%）因毒性而停止 ponatinib 治疗，36 例（71%）在食品和药物管理局警告/研究关闭后，1 例因不遵医嘱。达沙替尼是最常选择的二线 TKI（n=34；66%）。46 例可评估的患者中，44 例（96%）达到 CCyR，37 例（80%）达到主要分子反应，28 例（61%）达到 MR4，21 例（46%）达到 MR4.5。6 个月时 CCyR、主要分子反应、MR4 和 MR4.5 的累积 6 个月率分别为 96%、78%、50%和 36%。分别有 67%和 51%的患者达到了持续时间≥24 个月或≥60 个月的 MR4。24 个月时无事件生存率为 97%。中位随访 128 个月后，10 年总生存率为 90%。8 例（16%）患者发生 2-3 级严重心血管不良事件，导致 5 例（10%）患者永久性停药。
ponatinib 在新诊断的慢性期慢性髓性白血病中产生了高细胞遗传学和分子反应。但其在前线治疗中的应用受到动脉/血管阻塞和其他严重毒性的阻碍。
