NEJM:Ponatinib可用于难治性Ph阳性白血病的治疗
2012-11-29 NEJM NEJM
近日一项来自美国M.D.安德森癌症中心的研究表明，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。
近日一项来自美国M.D.安德森癌症中心的研究表明，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。
慢性髓性白血病（CML）患者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耐药通常由BCR-ABL激酶结构域突变所致。Ponatinib（AP24534）是一种有效的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均耐药的看门人（gatekeeper）突变体T315I]。
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。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。
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. 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. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.)
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#Nat#
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#Ph阳性#
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#难治性#
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#ponatinib#
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