Radioimmunotherapy for Lymphoma

描述（由申请人提供）：大多数非霍奇金淋巴瘤 (NHL)是CD 2 O + B淋巴细胞的恶性肿瘤。大约有55，000人 NHL的新病例每年;由于不明原因，发病率是 升中国一种治疗B细胞NHL的新方法是使用利妥昔单抗， 靶向CD 20抗原的单克隆抗体。钇-90是一种 可与抗CD 2 O抗体连接的放射性同位素，以靶向辐射 恶性B细胞初步研究已经建立了一个安全的单一 将产生肿瘤的钇-90抗CD 2 O抗体（Y2 B8）剂量 82%的低度或滤泡性NHL患者（pts）缓解。的 Y2 B8的主要毒性是可逆性骨髓抑制，导致 中性粒细胞减少症和血小板减少症以及伴随的 感染或出血。与抗CD 2 O抗体（In 2B 8）结合的铟-111 已经被开发用于预测肿瘤和正常器官的剂量测定。是 假设Y2 B8的再治疗在首次治疗后3-4个月进行， 剂量将改善完全缓解（CR）率以及持续时间 反应本提案的总体目标是开发一种安全的治疗方法 该策略使用两次连续剂量的Y2 B8，间隔12-16周。 在确定Y2 B8的最大耐受两个剂量（MTD）后， 将进行一项试验，以了解CR率是否可以增加一倍至50%。是 重要的是了解正常器官（包括骨髓）和肿瘤剂量学 在每次Y2 B8给药前使用In 2B 8扫描。统计模型使用 Tc放射性胶体扫描的In 2B 8剂量测定结果和骨髓质量计算 将进行研究，以了解是否可以预测骨髓毒性。的 In 2B 8扫描的结果将与计算机断层扫描（CT）相关联 和正电子发射断层扫描（PET）。CT和PET将对 在Y2 B8第二次给药时进行评价，因为许多患者有残留 CT检查发现肿块。据推测，如果残余质量是 In 2B 8或PET扫描呈阳性，这将代表残留淋巴瘤 而不是良性疤痕组织。由于骨髓抑制是主要的毒性， Y2 B8，假设这可以通过使用预防性药物来降低 集落刺激因子在确定MTD后，将增加患者 用预防性粒细胞巨噬细胞集落刺激因子治疗 （GM-CSF）和血小板生成生长因子（白细胞介素-II，oprelvekin）学习 骨髓抑制是否可以改善，Y2 B8的剂量是否 可以增加。将在Y2 B8前后进行骨髓检查， 评价骨髓毒性和对骨髓细胞遗传学的影响。虽然 人类不寻常地产生针对该抗体的抗体（人抗鼠抗体 抗小鼠抗体- HAMA），尚不清楚患者的HAMA是否会更高 在两次Y2 B8给药后，这一点将在本方案中进行检查。我们 预计这种新的放射免疫治疗方法将导致更多的 有效治疗NHL患者。

DESCRIPTION (Provided by applicant): The majority of non-Hodgkin's lymphomas (NHL) are malignancies of CD2O+ B-lymphocytes. There are approximately 55,000 new cases of NHL each year; and for unexplained reasons, the incidence is rising. A new form of treatment for B-cell NHL involves the use of rituximab, a monoclonal antibody that is targeted to the CD2O antigen. Yttrium-90 is a radioisotope that can be linked to the anti-CD2O antibody to target radiation to the malignant B-cells. Preliminary studies have established a safe single dose of Yttrium-90 anti-CD2O antibody (Y2B8) which will produce a tumor response in 82 percent of patients (pts) with low-grade or follicular NHL. The primary toxicity of Y2B8 is reversible myelosuppression, which results in neutropenia and thrombocytopenia and the concomitant increased risk for infection or bleeding. Indium-111 conjugated to the anti-CD2O antibody (In2B8) has been developed to predict tumor and normal organ dosimetry. It is hypothesized that retreatment with Y2B8 delivered 3-4 months after the first dose will improve the complete remission (CR) rate as well as the duration of response. The overall objective of this proposal is to develop a safe treatment strategy that utilizes two sequential doses of Y2B8 separated by 12-16 weeks. After the maximum tolerated two doses (MTD) of Y2B8 is established, a phase II trial will be done to learn if the CR rate can be doubled to 50 percent. It is important to learn the normal organ (including bone marrow) and tumor dosimetry using In2B8 scanning prior to each dose of Y2B8. Statistical models using the In2B8 dosimetry results and marrow mass calculations from Tc radiocolloid scans will be investigated to learn whether marrow toxicity can be predicted. The results of the In2B8 scans will be correlated with computerized tomography (CT) and positron emission tomography (PET) scans. CT and PET will be important to evaluate at the time of the second dose of Y2B8 because many pts have residual masses detected by CT. It is hypothesized that if the residual masses are positive by In2B8 or PET scanning that this will represent residual lymphoma rather than benign scar tissue. Since myelosuppression is the major toxicity of Y2B8, it is hypothesized that this can be decreased by utilizing prophylactic colony stimulating factors. After the MTD is established, additional pts will be treated with prophylactic granulocyte macrophage colony stimulating factor (GM-CSF) and thrombopoietic growth factor (Interleukin-II, oprelvekin) to learn whether the myelosuppression can be ameliorated and whether the dose of Y2B8 can be increased. Bone marrow exams will be performed before and after Y2B8 to evaluate marrow toxicity and effect on marrow cytogenetics. Although it is unusual for humans to develop an antibody to this antibody (human anti-murine anti-mouse antibody - HAMA), it is unknown whether pts will have a higher HAMA rate after two doses of Y2B8 and this will be examined in this protocol. We anticipate that this novel radioimmunotherapy approach will result in more effective treatment for pts with NHL.