NOVEL THERAPY FOR CHRONIC MYELOGENOUS LEUKEMIA

该提案的总体目标是开发一种新的治疗方法， 慢性粒细胞白血病（CML），通过增强移植物抗白血病 效应（GvL）。 GvL对BMT治疗的疗效至关重要， 慢性粒细胞白血病，但严重的发病率和死亡率的移植物抗宿主病 GvHD限制了我们有效使用Gvl的能力。 白细胞介素-1 受体拮抗剂（IL-1ra）限制了急性GvHD的死亡率 在小鼠模型中。 此外，IL-1ra抑制CML祖细胞生长 基于这些数据，在开发中的两步法 Gvl增强作为一种新的治疗CML的建议。 首先，一个阶段 II试验将进行，以确定是否干扰素-α加 供体淋巴细胞在CML患者中提供GvL效应， 同种异体骨髓移植后复发 初步数据显示， 输注可诱导血液学、细胞遗传学和分子遗传学 缓解。 不能检测到含有BRC/ABL转录本的细胞 使用非常敏感的聚合酶链反应（PCR）技术。 的 同样的技术是一种有效的方法来检测复发在非常早的 阶段，并提供机会，启动GvL时， 肿瘤负荷非常低。 为了实现这一目标， 建立定量PCR技术。 GvL效应很可能 与移植物抗宿主病有关 来自临床前小鼠的初步数据 模型表明，细胞因子失调是重要的， GvHD的病理生理学，如通过检测IL-1和TNF所证实的 急性GvHD期间皮肤和淋巴细胞中的α信息。 IL-1ra是 一种非常有效的预防和治疗实验性移植物抗宿主病的方法。 因此，这种方法的第二步是IL-12的I/II期试验。 1例对常规治疗无反应的急性GvHD患者 治疗 IL-1ra是这些患者中GvHD的特别有吸引力的疗法。 患者，因为它在体外抑制CML祖细胞生长，因此可能 增强GvL，而对正常造血没有影响。 期间 这些人研究了炎性细胞因子在诱导 并分析GvHD和GvL效应的维持。 这些研究 为最终目标打下基础：使用α-干扰素（ 降低CML负荷）、外周血淋巴细胞（诱导GvL）和 IL-1 ra（控制GvHD并限制CML祖细胞增殖）， 慢性粒细胞白血病的主要治疗。

The overall goal of this proposal is to develop a novel treatment for chronic myeloid leukemia (CML) by enhancing the graft-versus-leukemia effect (GvL). GvL is critical to the therapeutic efficacy of BMT for CML, but serious morbidity and mortality of graft-versus-host disease (GvHD) set limits on our ability to use Gvl effectively. Interleukin-1 receptor antagonist (IL-1ra) set limits on our mortality of acute GvHD in a murine model. In addition, IL-1ra inhibits CML progenitor growth in vitro Based on these data, a two-step approach in the development of Gvl enhancement as a new treatment for CML is proposed. First, a phase II trial will be performed to determine whether interferon-alpha plus donor lymphocytes provide a GvL effect in patients with CML that has relapsed after an allogeneic BMT. Preliminary data indicate that these infusions can induce hematologic, cytogenetic, and molecular genetic remissions. Cells containing brc/abl transcripts cannot be detected using a very sensitive polymerase chain reaction (PCR) technique. The same technique is an effective way to detect relapse at a very early stage, and provides the opportunity to initiate GvL at time when the tumor burden is very low. In order to accomplish this goal a quantitative PCR technique will be developed. The GvL effect is likely to be associated with GvHD. Preliminary data from the preclinical murine model suggest that cytokine dysregulation is important in the pathophysiology of GvHD, as demonstrated by the detection of IL-I and TNF alpha message in the skin and lymphocytes during acute GvHD. IL-1ra is a very effective means of preventing and treating experimental GvHD. Therefore, the second step to this approach is a phase I/II trial of IL- 1ra in patients with acute GvHD that is unresponsive to conventional treatment. IL-1ra is particularly attractive therapy for GvHD in these patients because it inhibits CML progenitor growth in vitro, and thus may enhance GvL, while having no effect on normal hematopoiesis. During these human studies the role of inflammatory cytokines in the induction and maintenance of GvHD and GvL effects will be analyzed. These studies lay the groundwork for the final goal: to use interferon-alpha (to reduce the CML burden), peripheral blood lymphocytes (to induce GvL) and IL-1ra (to control GvHD and limit CML progenitor proliferation) as primary therapy for CML.