A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.
A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.
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DOI：
10.1056/nejmoa1306494
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发表时间：
2013-11-07
期刊：
影响因子：
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通讯作者：
PACE Investigators
中科院分区：
文献类型：
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作者：
Cortes JE;Kim DW;Pinilla-Ibarz J;le Coutre P;Paquette R;Chuah C;Nicolini FE;Apperley JF;Khoury HJ;Talpaz M;DiPersio J;DeAngelo DJ;Abruzzese E;Rea D;Baccarani M;Müller MC;Gambacorti-Passerini C;Wong S;Lustgarten S;Rivera VM;Clackson T;Turner CD;Haluska FG;Guilhot F;Deininger MW;Hochhaus A;Hughes T;Goldman JM;Shah NP;Kantarjian H;PACE Investigators
Ponatinib是一种有效的口服酪氨酸激酶抑制剂，适用于未突变和突变的BCR-ABL，包括315位酪氨酸激酶抑制剂难治性苏氨酸-异亮氨酸突变的BCR-ABL （T315I）。我们在慢性髓性白血病（CML）或费城染色体阳性急性淋巴细胞白血病（ph阳性ALL）患者中进行了ponatinib的2期试验。我们招募了449名重度预处理的CML或ph阳性ALL患者，这些患者对达沙替尼或尼洛替尼有耐药性或不可接受的副作用，或患有BCR-ABL T315I突变。波纳替尼的初始剂量为45毫克，每日一次。中位随访时间为15个月。在267例慢性CML患者中，56%的患者有主要的细胞遗传学反应（51%的患者对达沙替尼或尼罗替尼有耐药性或不可接受的副作用，70%的患者有T315I突变），46%的患者有完全的细胞遗传学反应（两个亚组分别为40%和66%），34%的患者有主要的分子反应（两个亚组分别为27%和56%）。无论基线BCR-ABL激酶结构域突变状态如何，观察到的反应都是持久的；估计持续至少12个月的主要细胞遗传学反应率为91%。未检测到单一BCR-ABL突变对波纳替尼产生耐药性。在83例加速期CML患者中，55%有主要的血液学反应，39%有主要的细胞遗传学反应。在62例胚期CML患者中，31%有主要的血液学反应，23%有主要的细胞遗传学反应。在32例ph阳性ALL患者中，41%有主要的血液学反应，47%有主要的细胞遗传学反应。常见的不良事件有血小板减少（37%的患者）、皮疹（34%）、皮肤干燥（32%）和腹痛（22%）。9%的患者出现严重动脉血栓形成事件；3%的人认为这些事件与治疗有关。共有12%的患者因不良事件而停止治疗。波纳替尼在疾病分期和突变状态类别中具有显著的抗白血病活性。（由Ariad Pharmaceuticals和其他公司资助；PACE ClinicalTrials.gov编号：NCT01207440）
Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor–refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL). We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440.)