BCR-ABL激酶的突變經(jīng)常引起慢性髓性白血病(CML)和費城染色體陽性急性成淋巴細胞白血病(Ph-positive ALL)對酪氨酸激酶抑制劑的抗性,。Ponatinib (AP24534)是一種可阻斷野生型和突變型BCR-ABL基因的頗受矚目的口服酪氨酸激酶抑制劑藥物，其中包括看門基因(gatekeeper gene)T315I，后者可對酪氨酸激酶抑制劑藥物產(chǎn)生廣譜性抵抗性。近日一項來自美國M.D.安德森癌癥中心的Cortes博士等人的研究表明，Ponatinib在經(jīng)過多次預先治療的對酪氨酸激酶抑制劑耐藥的Ph陽性白血病患者（包括有BCR-ABL T315I突變,、其他突變或無突變的患者）中具有高度活性。相關研究于11月29日發(fā)表于新英格蘭醫(yī)學雜志（NEJM）上。
在這項1期劑量遞增研究中,，研究人員納入了81例有耐藥血液系統(tǒng)腫瘤的患者,，包括60例CML患者和5例Ph陽性ALL患者。給予ponatinib治療,，每日一次,，劑量范圍為2～60 mg。中位隨訪時間為56周（范圍,，2～140）,。
結(jié)果發(fā)現(xiàn)，劑量限制性毒性效應包括脂肪酶或淀粉酶水平升高和胰腺炎,。常見的不良反應為皮疹,、骨髓抑制以及全身癥狀。在Ph陽性患者中,，91%接受了≥2種已獲得批準的酪氨酸激酶抑制劑治療,，51%接受了所有3種已獲得批準的酪氨酸激酶抑制劑治療。研究人員發(fā)現(xiàn),，在43例慢性期CML患者中,，有98%出現(xiàn)完全血液學緩解，有72%出現(xiàn)主要細胞遺傳學緩解,，44%有主要分子學緩解,。在12例有T315I突變的慢性期CML患者中，100%有完全血液學緩解,，92%有主要細胞遺傳學緩解,。在13例未檢測到突變的慢性期CML患者中，100%有完全血液學緩解,，62%有主要細胞遺傳學緩解,。慢性期CML患者的緩解可持續(xù)。在22例加速期或急變期的CML患者或Ph陽性ALL患者中,，36%有主要血液學緩解,，32%有主要細胞遺傳學緩解。
研究人員最終得出結(jié)論,，Ponatinib在經(jīng)過多次預先治療的對酪氨酸激酶抑制劑耐藥的Ph陽性白血病患者中,，包括有BCR-ABL T315I突變、其他突變或無突變的患者,，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.
