ORIGINAL ARTICLE
Ponatinib in Refractory Philadelphia Chromosome–Positive Leukemias
Ponatinib可用于治疗难治性Ph染色体阳性白血病
Jorge E. Cortes, M.D., HagopKantarjian, M.D., Neil P. Shah, M.D., Ph.D., Dale Bixby, M.D., Ph.D., Michael J. Mauro, M.D., Ian Flinn, M.D., Ph.D., Thomas O'Hare, Ph.D., Simin Hu, Ph.D., Narayana I. Narasimhan, Ph.D., Victor M. Rivera, Ph.D., Tim Clackson, Ph.D., Christopher D. Turner, M.D., Frank G. Haluska, M.D., Ph.D., Brian J. Druker, M.D., Michael W.N. Deininger, M.D., Ph.D., and Moshe Talpaz, M.D.
N Engl J Med 2012; 367:2075-2088November 29, 2012DOI: 10.1056/NEJMoa1205127 Share:
BACKGROUND
Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. 背景
慢性粒细胞白血病(CML)和急性Ph染色体阳性淋巴细胞白血病(Ph阳性ALL)患者对酪氨酸激酶抑制剂的耐药性往往由BCR-ABL激酶结构域突变造成的。
Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocksnative and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors.
Ponatinib(AP24534)是一种有效的口服酪氨酸激酶抑制剂，阻碍天然型和突变型BCR-ABL，其中包括对酪氨酸激酶抑制剂均耐药的看门人突变体T315I。METHODS
In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. 方法
在这项1期剂量递增研究中，我们纳入了81例耐药性血癌患者，包括60例慢性粒细胞白血病和5例急性Ph染色体阳性淋巴细胞白血病。
Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140).
给予Ponatinib一天一次，剂量范围为2至60mg。中位随访时间为56周（范围2至140）。 RESULTS
Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. 结果
剂量毒性作用包括脂肪酶或淀粉酶水平升高以及胰腺炎。
Common adverse events were rash, myelosuppression, and constitutional symptoms. 常见不良反应为皮疹、骨髓抑制和全身症状。
Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors.
在Ph阳性患者中，91%接受了两种及以上的已获批准的酪氨酸激酶抑制剂，并且51%接受
了全部三种已获批准的酪氨酸激酶抑制剂。
Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response.
在43例慢性期CML患者中，98%出现完全血液学缓解，72%出现主要细胞遗传学缓解，以及44%出现主要分子生物学缓解。
Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response.
在12例T315I突变慢性期CML患者中，100%出现完全血液学缓解，以及92%出现主要细胞遗传学缓解。
Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. 在13例未检测到突变的慢性期CML患者中，100%出现完全血液学缓解，以及62%出现主要细胞遗传学缓解。
Responses among patients with chronic-phase CML were durable.
慢性期CML患者的缓解是持久的。
Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response.
在22例加速期或急变期的CML或Ph阳性ALL患者中，36%出现主要血液学缓解。32%出现主要细胞遗传学缓解。 CONCLUSIONS
Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.)
Ponatinib在治疗接受过大剂量化疗药物以及有酪氨酸激酶抑制剂耐药性的Ph阳性白血病患者中高度有效，包括带有BCR-ABL T315I突变、其他突变或无突变的患者。