Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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%).
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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%).
CONCLUSIONS: 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.
摘要：
背景：Ponatinib是第三代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。在这里，我们报道了ponatinib治疗慢性粒细胞白血病慢性期2期试验的长期随访.
方法：患者接受普纳替尼30-45mg/天。主要终点是6个月完全细胞遗传学应答(CCyR)的比率。该研究于2014年6月举行，因为心血管毒性的风险，要求患者更换TKI。
结果：51例患者接受了ponatinib治疗（中位剂量，45毫克/天）。中位年龄为48岁(范围，21-75）；30（59%）有基线心血管合并症。中位治疗时间为13个月(范围，2-25).14名患者（28%）因毒性而停药，36（71％）在食品和药物管理局警告/研究结束后，一个是不合规的。达沙替尼是最常选择的二线TKI（n=34;66％）。在6个月时可评估的46例患者中，44（96%）达到CCyR，37（80％）主要分子响应，28（61%）MR4和21（46%）MR4.5。CCyR的累计6个月利率，主要的分子反应，MR4和MR4.5为96%,78%,50%,36%,分别。在67％和51％的患者中观察到耐久MR4≥24或≥60个月，分别。24个月无事件生存率为97%。经过128个月的中位随访，10年总生存率为90%.8例患者（16%）有严重的2-3级心血管不良事件，导致五个（10%）永久停药。
结论：Ponatinib在新诊断的慢性粒细胞白血病慢性期中产生了较高的细胞遗传学和分子反应。其在前线设置中的使用受到动脉/血管闭塞和其他严重毒性的阻碍。
方法：患者接受普纳替尼30-45mg/天。主要终点是6个月完全细胞遗传学应答(CCyR)的比率。该研究于2014年6月举行，因为心血管毒性的风险，要求患者更换TKI。
结果：51例患者接受了ponatinib治疗（中位剂量，45毫克/天）。中位年龄为48岁(范围，21-75）；30（59%）有基线心血管合并症。中位治疗时间为13个月(范围，2-25).14名患者（28%）因毒性而停药，36（71％）在食品和药物管理局警告/研究结束后，一个是不合规的。达沙替尼是最常选择的二线TKI（n=34;66％）。在6个月时可评估的46例患者中，44（96%）达到CCyR，37（80％）主要分子响应，28（61%）MR4和21（46%）MR4.5。CCyR的累计6个月利率，主要的分子反应，MR4和MR4.5为96%,78%,50%,36%,分别。在67％和51％的患者中观察到耐久MR4≥24或≥60个月，分别。24个月无事件生存率为97%。经过128个月的中位随访，10年总生存率为90%.8例患者（16%）有严重的2-3级心血管不良事件，导致五个（10%）永久停药。
结论：Ponatinib在新诊断的慢性粒细胞白血病慢性期中产生了较高的细胞遗传学和分子反应。其在前线设置中的使用受到动脉/血管闭塞和其他严重毒性的阻碍。
