BCR-ABL激酶的突变经常引起慢性髓性白血病(CML)和费城染色体阳性急性成淋巴细胞白血病(Ph-positive ALL)对酪氨酸激酶抑制剂的抗性。Ponatinib (AP24534)是一种可阻断野生型和突变型BCR-ABL基因的颇受瞩目的口服酪氨酸激酶抑制剂药物，其中包括看门基因(gatekeeper gene)T315I，后者可对酪氨酸激酶抑制剂药物产生广谱性抵抗性。近日一项来自美国M.D.安德森癌症中心的Cortes博士等人的研究表明，Ponatinib在经过多次预先治疗的对酪氨酸激酶抑制剂耐药的Ph阳性白血病患者（包括有BCR-ABL T315I突变、其他突变或无突变的患者）中具有高度活性。相关研究于11月29日发表于新英格兰医学杂志（NEJM）上。
在这项1期剂量递增研究中，研究人员纳入了81例有耐药血液系统肿瘤的患者，包括60例CML患者和5例Ph阳性ALL患者。给予ponatinib治疗，每日一次，剂量范围为2～60 mg。中位随访时间为56周（范围，2～140）。
结果发现，剂量限制性毒性效应包括脂肪酶或淀粉酶水平升高和胰腺炎。常见的不良反应为皮疹、骨髓抑制以及全身症状。在Ph阳性患者中，91%接受了≥2种已获得批准的酪氨酸激酶抑制剂治疗，51%接受了所有3种已获得批准的酪氨酸激酶抑制剂治疗。研究人员发现，在43例慢性期CML患者中，有98%出现完全血液学缓解，有72%出现主要细胞遗传学缓解，44%有主要分子学缓解。在12例有T315I突变的慢性期CML患者中，100%有完全血液学缓解，92%有主要细胞遗传学缓解。在13例未检测到突变的慢性期CML患者中，100%有完全血液学缓解，62%有主要细胞遗传学缓解。慢性期CML患者的缓解可持续。在22例加速期或急变期的CML患者或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。
研究人员最终得出结论，Ponatinib在经过多次预先治疗的对酪氨酸激酶抑制剂耐药的Ph阳性白血病患者中，包括有BCR-ABL T315I突变、其他突变或无突变的患者，均具有高度活性。(生物谷Bioon.com)
DOI: 10.1056/NEJMoa1205127
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Ponatinib in Refractory Philadelphia Chromosome–Positive Leukemias
Jorge E. Cortes, M.D., Hagop Kantarjian, 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.
Background Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Phpositive 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. 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. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140). Results 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. 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.
