Radioimmunotherapy Based Transplant Regimens for Treatment of B-Cell Lymphoma and

复发仍然是许多接受自体或异体移植的患者失败的最重要原因。 移植用于治疗恶性淋巴瘤和急性髓性白血病。该项目将侧重于研究 放射免疫治疗靶向肿瘤相关抗原，作为预备方案的组成部分， 用于治疗这些疾病的自体和同种异体造血细胞移植。拟议 研究寻求提高抗肿瘤功效，以及降低该过程的毒性，这将延长治疗时间。 造血细胞移植（HCT）在老年患者中的应用，这些老年患者构成了大多数AML患者， 和淋巴瘤所提出的研究将调查结合至放射性标记的抗体的掺入。 靶向恶性B细胞上的CD 20抗原或恶性B细胞上的CD 33抗原的重金属放射性同位素（钇-90） AML和骨髓增生异常患者中的原始细胞。我们建议使用新的治疗方案进行五项临床研究， 用于AML和B细胞淋巴瘤的自体或同种异体移植：1）对于晚期淋巴瘤患者（低级别， 我们将继续研究高剂量90 Y标记的抗CD 20抗体联合 与依托泊苷和环磷酰胺在II期设置; 2）老年患者（年龄>60）复发性淋巴瘤 我们将把我们的I期观察扩展到90 Y标记的抗CD 20抗体与BEAM联合的II期研究， 化疗，以开发可安全用于该患者人群的有效方案; 3)还将开发90 Y标记的抗CD 20抗体作为降低强度的同种异体移植方案的一部分，用于不适合自体方法的淋巴瘤患者，包括复发性套细胞淋巴瘤、多发性复发性低度淋巴瘤或自体移植后复发的患者; 4）对于具有中高危细胞遗传学的AML患者，我们将启动90 Y标记抗CD 33抗体替代全身照射的研究，联合依托泊苷和环磷酰胺进行自体移植。 5）在完成I期安全性研究后，我们将用该方案进行II期研究。为 晚期白血病患者（早期复发、年龄较大、AML伴既往MDS、自体移植后复发），我们将 将所述90 Y标记的抗CD 33抗体掺入降低强度的同种异体移植方案中，以改善所述免疫应答。 这一高风险人群的治疗效果。这个项目的一般假设是， 作为自体和同种异体移植准备方案的组成部分， 通过减少HCT后疾病复发和降低毒性，从而延长HCT的潜在获益， 为更多患有这些疾病的患者提供治疗。

Relapse remains the most important cause of failure for many patients undergoing either autologous or allogeneic transplant for the treatment of malignant lymphoma and acute myelogenous leukemia. This project will focus on studies of radioimmunotherapy targeted to tumor-associated antigens, as a component of the preparatory regimens for autologous and allogeneic hematopoietic cell transplantation used in the treatment of these diseases. The proposed studies seek to improve the anti-tumor efficacy, as well as reduce the toxicity of the procedure which will extend the application of hematopoietic cell transplantation (HCT) to older patients who form the majority of patients with both AML and lymphoma. The proposed studies will investigate the incorporation of radiolabeled antibodies conjugated to a heavy metal radioisotope (Yttrium-90) that target either the CD20 antigen on malignant B-cells or the CD33 antigen on blasts in patients with AML and myelodysplasia. We propose to perform five clinical studies using novel regimens for autologous or allogeneic transplant for AML and B-cell lymphoma: 1) For patients with advanced lymphoma (low-grade, intermediate-grade, and mantle cell) we will continue our studies of high-dose 90Y-labeled anti-CD20 antibody combined with etoposide and cyclophosphamide in the Phase II setting; 2) For older patients (age>60) with relapsed lymphoma we will extend our Phase I observations to a Phase II study of 90Y-labeled anti-CD20 antibody combined with BEAM chemotherapy in order to develop an effective regimen that can be used safely in this population of patients; 3) 90Y-labeled anti-CD20 antibody will also be developed as part of a reduced intensity allogeneic transplant regimen for patients with lymphoma who are not candidates for an autologous approach, including those with relapsed mantle cell lymphoma, multiple relapsed low-grade lymphoma, or patients who have relapsed after autologous transplant; 4) For patients with AML, who have intermediate- and high-risk cytogenetics, we will initiate a study of 90Y-labeled anti-CD33 antibody to replace total body irradiation in combination with etoposide and cyclophosphamide for autologous transplant; 5) After completion of a Phase I safety study, we will conduct a Phase II study with this regimen. For patients with advanced leukemia (early relapse, older age, AML with prior MDS, relapse after auto-transplant), we will incorporate the 90Y-labeled anti-CD33 antibody into a reduced intensity allogeneic transplant regimen to improve the outcome for this high-risk population of patients. It is the general hypothesis of this project that targeted radiation therapy as a component of the autologous and allogeneic transplant preparative regimens will help improve therapeutic efficacy by decreasing post-HCT disease relapse and by reducing toxicity, thereby extending the potential benefit of treatment to a larger population of patients with these diseases.