Targeted Radiotherapy with 90Y-BC8 Monclonal Antibody, Fludarabine and TBI Follow

描述（由申请人提供）：在多发性骨髓瘤（MM）患者的治疗方面取得了重要进展。自体干细胞移植（ASCT）与常规治疗的随机试验已经证明了生存率的显著提高。与较老的诱导方案相比，沙利度胺、来那度胺和硼替佐米加ASCT的新型药物组合进一步提高了无进展生存期。然而，很少有MM患者在10年以上没有疾病进展。目前正在研究双重ASCT、ASCT后维持治疗或ASCT后异体移植等策略，以改善预后。同种异体干细胞移植（allo SCT）提供无肿瘤移植物和免疫，移植物抗骨髓瘤的效果。骨髓清除同种异体SCT治疗MM与15-30%的无病生存率相关，超过10年，这是治愈的最佳证据。然而，从历史上看，清骨髓同种异体SCT与移植相关死亡率（TRM）高达30-50%有关。低强度、非清髓性的同种异体SCT已被采用，可将死亡率降低至15-20%，但要取得成功，这种方法要求MM患者在同种异体SCT之前接受细胞减少治疗，通常是ASCT。然而，即使在连续的自体移植后，复发仍然是治疗失败的主要原因。因此，迫切需要改进的方法来更好地根除骨髓中残留的骨髓瘤细胞。我们已经证明131I-anti-CD45 (BC8) Ab对骨髓、脾脏和白血病部位的放射量至少是正常器官的2-3倍。我们进一步表明，高剂量131I-BC8 Ab可以安全地与非清髓方案联合用于老年髓系恶性肿瘤患者。虽然CD45在MM患者的肿瘤细胞上并不广泛表达，但CD45在所有其他白细胞上的广泛表达将允许有效靶向骨髓，MM的主要疾病部位。尽管131I在提供靶向放疗方面非常成功，由于131I的高γ辐射和131I相对较低的ss能量，对该技术的安全性和可移植性的担忧促使策略转变，在多发性骨髓瘤试验中使用90Y-BC8 Ab偶联物。90Y缺乏γ辐射，具有较高的ss能量和对骨骼的天然亲和力，应该是靶向骨髓的更好同位素。我们将使用111In-BC8 Ab进行剂量测定，以确定靶向骨髓的CD45多于非靶向组织（如肝、肺和肾）。接下来，患者将接受90Y-BC8的消融剂量，随后进行一段时间的同位素衰变，然后给予氟达拉滨90mg /m2，外部TBI 200cgy和来自HLA匹配的兄弟姐妹或非亲属供体的同种异体SCT。治疗方案将包括两个阶段的同位素剂量递增，旨在确定90Y抗cd45的最大耐受剂量，当接受同种异体SCT的MM患者联合氟达拉滨和TBI时。在非清髓性同种异体sct治疗方案中加入骨髓靶向放疗可以增加缓解并提高生存率。

DESCRIPTION (provided by applicant): Important progress has been made in the treatment of patients with multiple myeloma (MM). Randomized trials of autologous stem cell transplant (ASCT) v. conventional therapy alone have demonstrated significant improvements in survival. Novel drug combinations of thalidomide, lenalidomide and bortezomib plus ASCT have further improved progression-free survival compared older induction regimens. Nevertheless few patients with MM survive without disease progression beyond 10 years. Strategies such as double ASCT, maintenance therapy after ASCT or an allogeneic transplant after ASCT are being studied as ways to improve outcomes. Allogeneic stem cell transplant (allo SCT) provides a tumor-free graft and an immunologic, graft-versus- myeloma effect. Myeloablative allo SCT for MM is associated with a 15-30% probability of disease free survival extending beyond 10 years, the best evidence for cure. Myeloablative allo SCT is, however, historically associated with high transplant related mortality (TRM) of 30-50%. Less intensive, nonmyeloablative allo SCT has been adopted which can reduce mortality to 15-20%, but to be successful, this approach requires that patients with MM receive cytoreductive therapy usually with ASCT, prior to the allo SCT. Even after a tandem auto-allo SCT, however, relapses remain the principal cause of treatment failure. Thus, there is a critical need for improved ways to provide better eradication of residual myeloma cells in the bone marrow. We have shown that 131I-anti-CD45 (BC8) Ab can deliver at least 2-3-fold more radiation to marrow, spleen and sites of leukemia than to any normal organ. We have further shown that high-dose 131I-BC8 Ab can be safely combined with a non-myeloablative regimen in older patients with myeloid malignancies. While CD45 is not widely expressed on the tumor cells of patients with MM, the broad expression of CD45 on all other leukocytes will allow effective targeting to marrow, the principal disease site in MM. Although 131I has been highly successful with regard to delivering targeted radiotherapy, concerns about safety and the transportability of this technology due to high gamma emissions of 131I and the relatively low ss energy of 131I have prompted a shift in strategy to the use of a 90Y-BC8 Ab conjugate for trials in multiple myeloma. 90Y with its lack of gamma emissions, higher ss energy and natural affinity for bone, should be a better isotope for targeting marrow. We will perform dosimetry testing with 111In-BC8 Ab, to establish that more CD45 is targeted to marrow than non-target tissues such as liver, lung and kidneys. Patients will next receive an ablative dose of 90Y-BC8, followed by a period for isotope decay, then the administration of fludarabine 90 mg/m2, external TBI 200 cGY and allo SCT from an HLA matched sibling or unrelated donor. The treatment protocol will involve a 2-stage dose escalation of isotope in patients designed to determine the maximum tolerated dose of 90Y anti-CD45, when combined with fludarabine and TBI in patients with MM receiving allo SCT. Adding marrow targeted radiation to a nonmyeloablative allo-SCT regimen should increase remissions and improve survival.