Radioimmunotherapy for Leukemia

异基因造血细胞移植（HCT）是治疗血液系统恶性肿瘤的常用方法 因为疾病复发而失败。加强制备方案的尝试受到限制， 由于大多数调理剂的非特异性性质而引起的相关毒性。项目的总体目标 1是通过向白血病累及部位提供靶向治疗来克服这一限制， HCT后复发的风险，而不增加毒性。[131] L-抗CD 45抗体（Ab; BCS）可以将靶向辐射输送到造血组织， 淋巴结的转移是肝、肺或肾的2- 8倍。 这一观察结果已被转化为人类研究，证明了将[131]I- BC 8 Ab与氟达拉滨（FLU）和全身照射（TBI）的强度降低的准备方案， 晚期急性髓性白血病（AML）和高危骨髓增生异常综合征（MDS）患者。我们 现在提出三个具体目标来扩展这些初步意见。在目标1中，我们将执行 II期研究，以确定使用[131] I-BC 8 Ab与FLU和TBI组合在老年患者中的疗效， AML缓解期。在目标2中，我们将通过以下方式将这种方法扩展到缺乏HLA匹配供体的患者： 确定由[131] I-BC 8 Ab递送的辐射的最大耐受剂量（MTD）， 与采用2戈伊TBI、FLU和环磷酰胺的单倍相同HCT策略组合。我们将 然后进行单倍相合移植的II期研究，以评估其疗效， 方案.在目标3中，我们将在单中心经验的基础上进行多中心I期研究 估计当与FLU和2戈伊联合使用时，可通过[90] Y-BC 8 Ab输送的放射的MTD TBI作为老年晚期骨髓恶性肿瘤患者的准备方案，并确定 向其他机构输出这种方案的可行性。我们预计这些研究最终将 允许我们进行确定性的III期研究，其中同种异体HCT方法采用[131]I-或[90] Y-BC 8 将Ab与标准的降低强度和单倍相同的HCT方法进行比较。我们感到乐观 这些干预措施将提高急性白血病和骨髓增生异常患者的预后 通过提高反应率和存活率，同时最大限度地减少毒性。

Allogeneic hematopoietic cell transplantation (HCT) for treatment of hematological malignancies frequently fails because of disease recurrence. Attempts at intensifying the preparative regimen have been limited by associated toxicities due to the non-specific nature of most conditioning agents. The overall goal of Project 1 is to overcome this limitation by delivering targeted therapy to sites of leukemic involvement to decrease the risk of relapse after HCT without increased toxicity. We have shown that [131]l-anti-CD45 antibody (Ab; BCS) can deliver targeted radiation to hematopoietic tissues, with 2-3 times more radiation delivered to marrow, up to 12 times more to spleen, and 2- 8 times more to lymph nodes than to liver, lung or kidney. This observation has been translated to human studies that demonstrated the feasibility of combining [131]I- BC8 Ab with a reduced-intensity preparative regimen of fludarabine (FLU) and total body irradiation (TBI) in patients with advanced acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). We now propose three specific aims to extend these preliminary observations. In Aim 1 we will perform a phase II study to define the efficacy of using [131]l-BC8 Ab combined with FLU and TBI in older patients with AML in remission. In Aim 2 we will extend this approach to patients lacking HLA-matched donors by determining the maximally tolerated dose (MTD) of radiation delivered by [131]l-BC8 Ab that can be combined with a haplo-identical HCT strategy employing 2 Gy TBI, FLU, and cyclophosphamide. We will then conduct a phase II study of haplo-identical transplantation in order to estimate the efficacy of this regimen. In Aim 3, we will build on our single-center experience by performing a multi-center phase I study to estimate the MTD of radiation that can be delivered via [90]Y-BC8 Ab when combined with FLU and 2 Gy TBI as a preparative regimen for older patients with advanced myeloid malignancies, and to determine the feasibility of exporting such a regimen to other institutions. We anticipate that these studies will eventually allow us to carry out definitive Phase III studies in which allogeneic HCT approaches employing [131]I- or [90]Y-BC8 Ab are compared to standard reduced-intensity and haplo-identical HCT methods. We are optimistic that these interventions will enhance the prognosis for patients with acute leukemias and myelodysplasia by increasing the response and survival rates, while minimizing toxicities.