Ponatinib in refractory Philadelphia chromosome-positive leukemias.
Ponatinib in refractory Philadelphia chromosome-positive leukemias.
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DOI：
10.1056/nejmoa1205127
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发表时间：
2012-11-29
期刊：
影响因子：
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通讯作者：
Talpaz M
中科院分区：
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作者：
Cortes JE;Kantarjian H;Shah NP;Bixby D;Mauro MJ;Flinn I;O'Hare T;Hu S;Narasimhan NI;Rivera VM;Clackson T;Turner CD;Haluska FG;Druker BJ;Deininger MW;Talpaz M
慢性粒细胞白血病（CML）和费城染色体阳性急性淋巴细胞白血病（Ph阳性ALL）患者对酪氨酸激酶抑制剂的耐药性通常是由BCR-ABL激酶结构域突变引起的。Ponatinib（AP 24534）是一种强效口服酪氨酸激酶抑制剂，可阻断天然和突变的BCR-ABL，包括对酪氨酸激酶抑制剂一致耐药的看门突变体T315 I。在这项1期剂量递增研究中，我们招募了81例耐药血液系统癌症患者，包括60例CML患者和5例Ph阳性ALL患者。泊那替尼每日给药一次，剂量范围为2 - 60 mg。中位随访时间为56周（范围：2 - 140周）。剂量限制性毒性作用包括脂肪酶或淀粉酶水平升高和胰腺炎。常见的不良事件为皮疹、骨髓抑制和全身症状。在Ph阳性患者中，91%接受过两种或更多种批准的酪氨酸激酶抑制剂，51%接受过所有三种批准的酪氨酸激酶抑制剂。在43例慢性期CML患者中，98%有完全血液学缓解，72%有主要细胞遗传学缓解，44%有主要分子学缓解。在12例T315 I突变的慢性期CML患者中，100%的患者有完全的血液学缓解，92%的患者有主要的细胞遗传学缓解。在13例慢性期CML患者中，没有检测到突变，100%有完全的血液学缓解，62%有主要的细胞遗传学缓解。慢性期CML患者的反应是持久的。在22例加速期或急变期CML或Ph阳性ALL患者中，36%有主要血液学缓解，32%有主要细胞遗传学缓解。泊那替尼在对酪氨酸激酶抑制剂耐药的重度预治疗Ph阳性白血病患者中具有高度活性，包括携带BCR-ABL T315 I突变、其他突变或无突变的患者。（由Ariad Pharmaceuticals和其他公司资助; ClinicalTrials.gov编号，NCT 00660920。
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. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors. 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. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140). Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. 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. 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. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. 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. 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.)