Improving the Outcome of Patients with Chronic Myeloid Leukemia Through Medi

该项目的主要目的是为慢性粒细胞白血病患者确定改进的治疗方案。伊马替尼是CML的标准治疗，但近20%的患者从未实现完全的细胞遗传学缓解，大多数患者通过聚合酶链反应遗留疾病，10-15%的缓解患者最终进展。更有效的酪氨酸激酶抑制剂（TKI）如达沙替尼和尼洛替尼在伊马替尼失效后具有显著的临床活性。第一个目的是确定达沙替尼或尼洛替尼是否可以改善新诊断的慢性期CML患者的分子反应、无事件和无进展生存期。患者将在两个平行研究中的一个中接受治疗，主要目的是提高12个月时的分子反应率。第二个目的是研究PRI疫苗形式的免疫治疗是否可以改善伊马替尼治疗的微小残留病患者的分子反应。由于干扰素可以改善PRI的来源蛋白酶3的表达，因此具有这种表型的患者将随机接受PRI和伊马替尼，有或没有干扰素。主要目标是改善PRI疫苗的分子反应。基于该资助的数据表明JAK2在bcr - abl阳性细胞中活化，第三个目的是研究JAK2抑制是否对TKI难治性CML患者具有临床活性。我们将在至少2次TKI治疗失败的患者中开展JAK2抑制剂INCB18424的2期临床试验。长期计划是联合TKI使用该药。第四个目标处理的是blast期患者的问题，这是一组治疗效果不佳的患者。达沙替尼的反应率很高，但大多数患者最终会复发。甲基化增加与CML的进展有关。因此，我们将用地西他滨（一种低甲基化药物）和达沙替尼治疗爆炸期CML患者，以确定这种组合是否可以提高爆炸期CML的反应率和持久性。总的来说，该项目可能会改善所有疾病阶段患者的长期预后，并使我们更接近完全根除CML。

The main objective of this project is to identify improved therapeutic options for patients with CML. Imatinib is standard therapy for CML, but nearly 20% of patients never achieve complete cytogenetic remission, and most have residual disease by polymerase chain reaction, and 10-15% of those who achieve remission eventually progress. More potent tyrosine kinase inhibitors (TKI) such as dasatinib and nilotinib have significant clinical activity after imatinib failure. The first aim is to determine whether dasatinib or nilotinib may improve the molecular response, and event-free and progression-free survival of patients with newly diagnosed chronic phase CML. Patients will be treated in one of two parallel studies with the primary objective to improve the molecular response rate at 12 months. The second aim is to investigate whether immunotherapy, in the form of PRI vaccine, can improve molecular responses of patients with minimal residual disease on imatinib therapy. Because Interferon may improve the expression of proteinase 3 from which PRI is derived, patients with this phenotype will be randomized to receive PRI and imatinib, with or without interferon. The primary objective is to improve the molecular response with PRI vaccine. Based on data originated through this grant suggesting activation of JAK2 in Bcr-Abl-positive cells, the third aim is to investigate whether JAK2 inhibition may have clinical activity in CML patients refractory to TKI. We will conduct a phase 2 trial of INCB18424, a JAK2 inhibitor, in patients who failed at least 2 TKI. The long-term plan is to use this agent in combination with TKI. The fourth aim deals with the problem of patients with blast phase, a group with dismal outcome with available therapy. Dasatinib induces high response rates but most patients eventually relapse. Increased methylation is associated with progression in CML. We will thus treat patients with blast phase CML with decitabine, a hypomethylating agent, and dasatinib to determine whether this combination may improve the rate and durability of responses in blast phase CML. Overall, this project may lead to improved long-term outcome for patients with all phases ofthe disease and get us closer to complete eradication of CML.